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Cummings)] TJ ET 0.271 0.267 0.267 rg BT 193.121 638.299 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 198.542 638.299 Td /F1 9.8 Tf [(Miriam A. Hickey)] TJ ET 0.271 0.267 0.267 rg BT 271.667 638.299 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 277.088 638.299 Td /F1 9.8 Tf [(Max Kleiman-Weiner)] TJ ET 0.271 0.267 0.267 rg BT 367.558 638.299 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 372.979 638.299 Td /F1 9.8 Tf [(Jane Chen)] TJ ET 0.271 0.267 0.267 rg BT 420.130 638.299 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 425.551 638.299 Td /F1 9.8 Tf [(Joseph B. Watson)] TJ ET 0.271 0.267 0.267 rg BT 504.673 638.299 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 510.094 638.299 Td /F1 9.8 Tf [(Michael S. )] TJ ET BT 26.250 626.394 Td /F1 9.8 Tf [(Levine)] TJ ET 0.271 0.267 0.267 rg BT 26.250 614.490 Td /F1 9.8 Tf [(Cepeda C, Cummings DM, Hickey MA, Kleiman-Weiner M, Chen J, Watson JB, Levine MS. Rescuing the Corticostriatal )] TJ ET BT 26.250 602.585 Td /F1 9.8 Tf [(Synaptic Disconnection in the R6/2 Mouse Model of Huntingtons Disease: Exercise, Adenosine Receptors and Ampakines. )] TJ ET BT 26.250 590.680 Td /F1 9.8 Tf [(PLOS Currents Huntington Disease. 2010 Sep 20 . Edition 1. doi: 10.1371/currents.RRN1182.)] TJ ET q 15.000 30.177 577.500 558.122 re W n 0.271 0.267 0.267 rg BT 26.250 561.578 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 541.623 Td /F1 9.8 Tf [(In the R6/2 mouse model of Huntingtons disease \(HD\) we examined the effects of a number of behavioral and pharmacological )] TJ ET BT 26.250 529.719 Td /F1 9.8 Tf [(manipulations aimed at rescuing the progressive loss of synaptic communication between cerebral cortex and striatum. Two )] TJ ET BT 26.250 517.814 Td /F1 9.8 Tf [(cohorts of transgenic mice with ~110 and 210 CAG repeats were utilized. Exercise prevented the reduction in striatal medium-)] TJ ET BT 26.250 505.909 Td /F1 9.8 Tf [(sized spiny neuron membrane capacitance but did not reestablish synaptic communication. Activation of adenosine A2A type )] TJ ET BT 26.250 494.004 Td /F1 9.8 Tf [(receptors renormalized postsynaptic activity to some extent. Finally, the ampakine Cx614, which has been shown to prevent ?-)] TJ ET BT 26.250 482.100 Td /F1 9.8 Tf [(amino-3-hydroxyl-5-methyl-4-isoxazole-propionate \(AMPA\) receptor desensitization, slow deactivation, and facilitate glutamate )] TJ ET BT 26.250 470.195 Td /F1 9.8 Tf [(release, induced significant increases in synaptic activity, albeit the effect was somewhat reduced in fully symptomatic, )] TJ ET BT 26.250 458.290 Td /F1 9.8 Tf [(compared to control mice. With some limitations, each of these strategies can be used to delay and partially rescue phenotypic )] TJ ET BT 26.250 446.385 Td /F1 9.8 Tf [(progression of HD in this model.)] TJ ET BT 26.250 409.783 Td /F4 12.0 Tf [(Funding Statement)] TJ ET BT 26.250 389.829 Td /F1 9.8 Tf [(This study was supported by grants from the USPHS \(NS41574\), the High Q Foundation, the Cure HD Initiative and the )] TJ ET BT 26.250 377.924 Td /F1 9.8 Tf [(Hereditary Disease Foundation.)] TJ ET BT 26.250 348.821 Td /F4 12.0 Tf [(Introduction)] TJ ET BT 26.250 328.867 Td /F1 9.8 Tf [(Huntingtons disease \(HD\) is an insidious, progressive and fatal neurodegenerative disorder caused by a mutation that expands )] TJ ET BT 26.250 316.962 Td /F1 9.8 Tf [(the number of CAG \(glutamine\) repeats )] TJ ET 0.267 0.267 0.267 rg BT 199.654 316.962 Td /F1 9.8 Tf [([1])] TJ ET 0.271 0.267 0.267 rg BT 210.496 316.962 Td /F1 9.8 Tf [( . Neuropathologically, HD is characterized by loss of striatal medium-sized spiny )] TJ ET BT 26.250 305.058 Td /F1 9.8 Tf [(neurons \(MSSNs\), as well as more discrete cell loss in other brain areas )] TJ ET 0.267 0.267 0.267 rg BT 340.512 305.058 Td /F1 9.8 Tf [([2])] TJ ET 0.271 0.267 0.267 rg BT 351.354 305.058 Td /F1 9.8 Tf [( . The symptoms include motor abnormalities, the )] TJ ET BT 26.250 293.153 Td /F1 9.8 Tf [(more prominent being chorea, as well as cognitive and psychiatric disturbances )] TJ ET 0.267 0.267 0.267 rg BT 371.429 293.153 Td /F1 9.8 Tf [([3])] TJ ET 0.271 0.267 0.267 rg BT 382.271 293.153 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 273.748 Td /F1 9.8 Tf [(Genetic mouse models of HD recapitulate some, but not all, of the phenotypic alterations found in human HD )] TJ ET 0.267 0.267 0.267 rg BT 497.721 273.748 Td /F1 9.8 Tf [([4])] TJ ET 0.271 0.267 0.267 rg BT 508.563 273.748 Td /F1 9.8 Tf [( . In particular, )] TJ ET BT 26.250 261.843 Td /F1 9.8 Tf [(the R6/2 model with ~150 CAG repeats has provided a wealth of information about mechanisms of disease progression and )] TJ ET BT 26.250 249.939 Td /F1 9.8 Tf [(represents a useful tool for drug screening as the progression of the phenotype occurs rapidly )] TJ ET 0.267 0.267 0.267 rg BT 432.698 249.939 Td /F1 9.8 Tf [([5])] TJ ET 0.271 0.267 0.267 rg BT 443.540 249.939 Td /F1 9.8 Tf [( and motor, histopathological, )] TJ ET BT 26.250 238.034 Td /F1 9.8 Tf [(and neuronal functional changes are reliable markers of the disease.)] TJ ET BT 26.250 218.629 Td /F1 9.8 Tf [(Our laboratory has characterized a number of morphological and electrophysiological alterations in striatum and cortex of these )] TJ ET BT 26.250 206.724 Td /F1 9.8 Tf [(mice )] TJ ET 0.267 0.267 0.267 rg BT 49.543 206.724 Td /F1 9.8 Tf [([6])] TJ ET BT 60.385 206.724 Td /F1 9.8 Tf [([7])] TJ ET 0.271 0.267 0.267 rg BT 71.227 206.724 Td /F1 9.8 Tf [( . We demonstrated reduced membrane capacitance and increased input resistance in neurons from symptomatic )] TJ ET BT 26.250 194.820 Td /F1 9.8 Tf [(R6/2 mice, along with decreases in somatic size, dendritic field, and number of spines of striatal MSSNs and cortical pyramidal )] TJ ET BT 26.250 182.915 Td /F1 9.8 Tf [(neurons )] TJ ET 0.267 0.267 0.267 rg BT 64.187 182.915 Td /F1 9.8 Tf [([8])] TJ ET 0.271 0.267 0.267 rg BT 75.029 182.915 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 163.510 Td /F1 9.8 Tf [(In addition, synaptic changes along the corticostriatal pathway occur )] TJ ET 0.267 0.267 0.267 rg BT 323.225 163.510 Td /F1 9.8 Tf [([8])] TJ ET BT 334.067 163.510 Td /F1 9.8 Tf [([9])] TJ ET BT 344.909 163.510 Td /F1 9.8 Tf [([10])] TJ ET 0.271 0.267 0.267 rg BT 361.172 163.510 Td /F1 9.8 Tf [( . An early and a late synaptic phenotype can be )] TJ ET BT 26.250 151.605 Td /F1 9.8 Tf [(characterized in striatal MSSNs. Early, synaptic dysregulation of glutamate release is manifested by the occurrence of large-)] TJ ET BT 26.250 139.701 Td /F1 9.8 Tf [(amplitude spontaneous excitatory postsynaptic currents \(EPSCs\) that reflect cortical hyperexcitability. Such increased )] TJ ET BT 26.250 127.796 Td /F1 9.8 Tf [(excitability could explain the propensity to seize and the lower convulsive threshold to systemic administration of epileptogenic )] TJ ET BT 26.250 115.891 Td /F1 9.8 Tf [(agents in R6/2 mice )] TJ ET 0.267 0.267 0.267 rg BT 115.121 115.891 Td /F1 9.8 Tf [([11])] TJ ET 0.271 0.267 0.267 rg BT 131.384 115.891 Td /F1 9.8 Tf [( . Large synaptic events in MSSNs can be reduced by riluzole and valproic acid )] TJ ET 0.267 0.267 0.267 rg BT 475.491 115.891 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 486.333 115.891 Td /F1 9.8 Tf [( and cortical )] TJ ET BT 26.250 103.986 Td /F1 9.8 Tf [(hyperexcitability can be renormalized by anticonvulsant agents such as rolipram and tiagabine )] TJ ET 0.267 0.267 0.267 rg BT 434.843 103.986 Td /F1 9.8 Tf [([12])] TJ ET BT 451.106 103.986 Td /F1 9.8 Tf [([13])] TJ ET 0.271 0.267 0.267 rg BT 467.369 103.986 Td /F1 9.8 Tf [( . Similarly, reducing )] TJ ET BT 26.250 92.082 Td /F1 9.8 Tf [(glutamatergic transmission by decortication around 4-6 weeks of age can be beneficial in R6/2 mice )] TJ ET 0.267 0.267 0.267 rg BT 458.682 92.082 Td /F1 9.8 Tf [([14])] TJ ET 0.271 0.267 0.267 rg BT 474.945 92.082 Td /F1 9.8 Tf [( . However, at about 5-)] TJ ET BT 26.250 80.177 Td /F1 9.8 Tf [(7 weeks of age, a progressive reduction in the frequency of spontaneous EPSCs in MSSNs occurs, leading to a virtual )] TJ ET BT 26.250 68.272 Td /F1 9.8 Tf [(disconnection between cortex and striatum )] TJ ET 0.267 0.267 0.267 rg BT 213.752 68.272 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 224.594 68.272 Td /F1 9.8 Tf [( . This disconnection is deleterious as it deprives the striatum of essential trophic )] TJ ET BT 26.250 56.367 Td /F1 9.8 Tf [(factors produced by cortical pyramidal neurons, such as brain-derived neurotrophic factor \(BDNF\), and could also result in a )] TJ ET BT 26.250 44.463 Td /F1 9.8 Tf [(deficit in survival signaling by synaptic N-methyl-D-aspartate \(NMDA\) receptors and preferential activation of proapoptotic )] TJ ET Q q 15.000 659.406 577.500 78.594 re W n 0.267 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(Rescuing the Corticostriatal Synaptic Disconnection in the R6/2 )] TJ ET BT 15.000 693.094 Td /F2 21.0 Tf [(Mouse Model of Huntingtons Disease: Exercise, Adenosine )] TJ ET BT 15.000 668.146 Td /F2 21.0 Tf [(Receptors and Ampakines)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 650.140 Td /F3 9.8 Tf [(September 20, 2010)] TJ ET 0.267 0.267 0.267 rg BT 26.250 638.299 Td /F1 9.8 Tf [(Carlos Cepeda)] TJ ET 0.271 0.267 0.267 rg BT 91.273 638.299 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 96.694 638.299 Td /F1 9.8 Tf [(Damian M. Cummings)] TJ ET 0.271 0.267 0.267 rg BT 193.121 638.299 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 198.542 638.299 Td /F1 9.8 Tf [(Miriam A. Hickey)] TJ ET 0.271 0.267 0.267 rg BT 271.667 638.299 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 277.088 638.299 Td /F1 9.8 Tf [(Max Kleiman-Weiner)] TJ ET 0.271 0.267 0.267 rg BT 367.558 638.299 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 372.979 638.299 Td /F1 9.8 Tf [(Jane Chen)] TJ ET 0.271 0.267 0.267 rg BT 420.130 638.299 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 425.551 638.299 Td /F1 9.8 Tf [(Joseph B. Watson)] TJ ET 0.271 0.267 0.267 rg BT 504.673 638.299 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 510.094 638.299 Td /F1 9.8 Tf [(Michael S. )] TJ ET BT 26.250 626.394 Td /F1 9.8 Tf [(Levine)] TJ ET 0.271 0.267 0.267 rg BT 26.250 614.490 Td /F1 9.8 Tf [(Cepeda C, Cummings DM, Hickey MA, Kleiman-Weiner M, Chen J, Watson JB, Levine MS. Rescuing the Corticostriatal )] TJ ET BT 26.250 602.585 Td /F1 9.8 Tf [(Synaptic Disconnection in the R6/2 Mouse Model of Huntingtons Disease: Exercise, Adenosine Receptors and Ampakines. )] TJ ET BT 26.250 590.680 Td /F1 9.8 Tf [(PLOS Currents Huntington Disease. 2010 Sep 20 . Edition 1. doi: 10.1371/currents.RRN1182.)] TJ ET q 15.000 30.177 577.500 558.122 re W n 0.271 0.267 0.267 rg BT 26.250 561.578 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 541.623 Td /F1 9.8 Tf [(In the R6/2 mouse model of Huntingtons disease \(HD\) we examined the effects of a number of behavioral and pharmacological )] TJ ET BT 26.250 529.719 Td /F1 9.8 Tf [(manipulations aimed at rescuing the progressive loss of synaptic communication between cerebral cortex and striatum. Two )] TJ ET BT 26.250 517.814 Td /F1 9.8 Tf [(cohorts of transgenic mice with ~110 and 210 CAG repeats were utilized. Exercise prevented the reduction in striatal medium-)] TJ ET BT 26.250 505.909 Td /F1 9.8 Tf [(sized spiny neuron membrane capacitance but did not reestablish synaptic communication. Activation of adenosine A2A type )] TJ ET BT 26.250 494.004 Td /F1 9.8 Tf [(receptors renormalized postsynaptic activity to some extent. Finally, the ampakine Cx614, which has been shown to prevent ?-)] TJ ET BT 26.250 482.100 Td /F1 9.8 Tf [(amino-3-hydroxyl-5-methyl-4-isoxazole-propionate \(AMPA\) receptor desensitization, slow deactivation, and facilitate glutamate )] TJ ET BT 26.250 470.195 Td /F1 9.8 Tf [(release, induced significant increases in synaptic activity, albeit the effect was somewhat reduced in fully symptomatic, )] TJ ET BT 26.250 458.290 Td /F1 9.8 Tf [(compared to control mice. With some limitations, each of these strategies can be used to delay and partially rescue phenotypic )] TJ ET BT 26.250 446.385 Td /F1 9.8 Tf [(progression of HD in this model.)] TJ ET BT 26.250 409.783 Td /F4 12.0 Tf [(Funding Statement)] TJ ET BT 26.250 389.829 Td /F1 9.8 Tf [(This study was supported by grants from the USPHS \(NS41574\), the High Q Foundation, the Cure HD Initiative and the )] TJ ET BT 26.250 377.924 Td /F1 9.8 Tf [(Hereditary Disease Foundation.)] TJ ET BT 26.250 348.821 Td /F4 12.0 Tf [(Introduction)] TJ ET BT 26.250 328.867 Td /F1 9.8 Tf [(Huntingtons disease \(HD\) is an insidious, progressive and fatal neurodegenerative disorder caused by a mutation that expands )] TJ ET BT 26.250 316.962 Td /F1 9.8 Tf [(the number of CAG \(glutamine\) repeats )] TJ ET 0.267 0.267 0.267 rg BT 199.654 316.962 Td /F1 9.8 Tf [([1])] TJ ET 0.271 0.267 0.267 rg BT 210.496 316.962 Td /F1 9.8 Tf [( . Neuropathologically, HD is characterized by loss of striatal medium-sized spiny )] TJ ET BT 26.250 305.058 Td /F1 9.8 Tf [(neurons \(MSSNs\), as well as more discrete cell loss in other brain areas )] TJ ET 0.267 0.267 0.267 rg BT 340.512 305.058 Td /F1 9.8 Tf [([2])] TJ ET 0.271 0.267 0.267 rg BT 351.354 305.058 Td /F1 9.8 Tf [( . The symptoms include motor abnormalities, the )] TJ ET BT 26.250 293.153 Td /F1 9.8 Tf [(more prominent being chorea, as well as cognitive and psychiatric disturbances )] TJ ET 0.267 0.267 0.267 rg BT 371.429 293.153 Td /F1 9.8 Tf [([3])] TJ ET 0.271 0.267 0.267 rg BT 382.271 293.153 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 273.748 Td /F1 9.8 Tf [(Genetic mouse models of HD recapitulate some, but not all, of the phenotypic alterations found in human HD )] TJ ET 0.267 0.267 0.267 rg BT 497.721 273.748 Td /F1 9.8 Tf [([4])] TJ ET 0.271 0.267 0.267 rg BT 508.563 273.748 Td /F1 9.8 Tf [( . In particular, )] TJ ET BT 26.250 261.843 Td /F1 9.8 Tf [(the R6/2 model with ~150 CAG repeats has provided a wealth of information about mechanisms of disease progression and )] TJ ET BT 26.250 249.939 Td /F1 9.8 Tf [(represents a useful tool for drug screening as the progression of the phenotype occurs rapidly )] TJ ET 0.267 0.267 0.267 rg BT 432.698 249.939 Td /F1 9.8 Tf [([5])] TJ ET 0.271 0.267 0.267 rg BT 443.540 249.939 Td /F1 9.8 Tf [( and motor, histopathological, )] TJ ET BT 26.250 238.034 Td /F1 9.8 Tf [(and neuronal functional changes are reliable markers of the disease.)] TJ ET BT 26.250 218.629 Td /F1 9.8 Tf [(Our laboratory has characterized a number of morphological and electrophysiological alterations in striatum and cortex of these )] TJ ET BT 26.250 206.724 Td /F1 9.8 Tf [(mice )] TJ ET 0.267 0.267 0.267 rg BT 49.543 206.724 Td /F1 9.8 Tf [([6])] TJ ET BT 60.385 206.724 Td /F1 9.8 Tf [([7])] TJ ET 0.271 0.267 0.267 rg BT 71.227 206.724 Td /F1 9.8 Tf [( . We demonstrated reduced membrane capacitance and increased input resistance in neurons from symptomatic )] TJ ET BT 26.250 194.820 Td /F1 9.8 Tf [(R6/2 mice, along with decreases in somatic size, dendritic field, and number of spines of striatal MSSNs and cortical pyramidal )] TJ ET BT 26.250 182.915 Td /F1 9.8 Tf [(neurons )] TJ ET 0.267 0.267 0.267 rg BT 64.187 182.915 Td /F1 9.8 Tf [([8])] TJ ET 0.271 0.267 0.267 rg BT 75.029 182.915 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 163.510 Td /F1 9.8 Tf [(In addition, synaptic changes along the corticostriatal pathway occur )] TJ ET 0.267 0.267 0.267 rg BT 323.225 163.510 Td /F1 9.8 Tf [([8])] TJ ET BT 334.067 163.510 Td /F1 9.8 Tf [([9])] TJ ET BT 344.909 163.510 Td /F1 9.8 Tf [([10])] TJ ET 0.271 0.267 0.267 rg BT 361.172 163.510 Td /F1 9.8 Tf [( . An early and a late synaptic phenotype can be )] TJ ET BT 26.250 151.605 Td /F1 9.8 Tf [(characterized in striatal MSSNs. Early, synaptic dysregulation of glutamate release is manifested by the occurrence of large-)] TJ ET BT 26.250 139.701 Td /F1 9.8 Tf [(amplitude spontaneous excitatory postsynaptic currents \(EPSCs\) that reflect cortical hyperexcitability. Such increased )] TJ ET BT 26.250 127.796 Td /F1 9.8 Tf [(excitability could explain the propensity to seize and the lower convulsive threshold to systemic administration of epileptogenic )] TJ ET BT 26.250 115.891 Td /F1 9.8 Tf [(agents in R6/2 mice )] TJ ET 0.267 0.267 0.267 rg BT 115.121 115.891 Td /F1 9.8 Tf [([11])] TJ ET 0.271 0.267 0.267 rg BT 131.384 115.891 Td /F1 9.8 Tf [( . Large synaptic events in MSSNs can be reduced by riluzole and valproic acid )] TJ ET 0.267 0.267 0.267 rg BT 475.491 115.891 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 486.333 115.891 Td /F1 9.8 Tf [( and cortical )] TJ ET BT 26.250 103.986 Td /F1 9.8 Tf [(hyperexcitability can be renormalized by anticonvulsant agents such as rolipram and tiagabine )] TJ ET 0.267 0.267 0.267 rg BT 434.843 103.986 Td /F1 9.8 Tf [([12])] TJ ET BT 451.106 103.986 Td /F1 9.8 Tf [([13])] TJ ET 0.271 0.267 0.267 rg BT 467.369 103.986 Td /F1 9.8 Tf [( . Similarly, reducing )] TJ ET BT 26.250 92.082 Td /F1 9.8 Tf [(glutamatergic transmission by decortication around 4-6 weeks of age can be beneficial in R6/2 mice )] TJ ET 0.267 0.267 0.267 rg BT 458.682 92.082 Td /F1 9.8 Tf [([14])] TJ ET 0.271 0.267 0.267 rg BT 474.945 92.082 Td /F1 9.8 Tf [( . However, at about 5-)] TJ ET BT 26.250 80.177 Td /F1 9.8 Tf [(7 weeks of age, a progressive reduction in the frequency of spontaneous EPSCs in MSSNs occurs, leading to a virtual )] TJ ET BT 26.250 68.272 Td /F1 9.8 Tf [(disconnection between cortex and striatum )] TJ ET 0.267 0.267 0.267 rg BT 213.752 68.272 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 224.594 68.272 Td /F1 9.8 Tf [( . This disconnection is deleterious as it deprives the striatum of essential trophic )] TJ ET BT 26.250 56.367 Td /F1 9.8 Tf [(factors produced by cortical pyramidal neurons, such as brain-derived neurotrophic factor \(BDNF\), and could also result in a )] TJ ET BT 26.250 44.463 Td /F1 9.8 Tf [(deficit in survival signaling by synaptic N-methyl-D-aspartate \(NMDA\) receptors and preferential activation of proapoptotic )] TJ ET Q q 15.000 659.406 577.500 78.594 re W n 0.267 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(Rescuing the Corticostriatal Synaptic Disconnection in the R6/2 )] TJ ET BT 15.000 693.094 Td /F2 21.0 Tf [(Mouse Model of Huntingtons Disease: Exercise, Adenosine )] TJ ET BT 15.000 668.146 Td /F2 21.0 Tf [(Receptors and Ampakines)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 650.140 Td /F3 9.8 Tf [(September 20, 2010)] TJ ET 0.267 0.267 0.267 rg BT 26.250 638.299 Td /F1 9.8 Tf [(Carlos Cepeda)] TJ ET 0.271 0.267 0.267 rg BT 91.273 638.299 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 96.694 638.299 Td /F1 9.8 Tf [(Damian M. Cummings)] TJ ET 0.271 0.267 0.267 rg BT 193.121 638.299 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 198.542 638.299 Td /F1 9.8 Tf [(Miriam A. Hickey)] TJ ET 0.271 0.267 0.267 rg BT 271.667 638.299 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 277.088 638.299 Td /F1 9.8 Tf [(Max Kleiman-Weiner)] TJ ET 0.271 0.267 0.267 rg BT 367.558 638.299 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 372.979 638.299 Td /F1 9.8 Tf [(Jane Chen)] TJ ET 0.271 0.267 0.267 rg BT 420.130 638.299 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 425.551 638.299 Td /F1 9.8 Tf [(Joseph B. Watson)] TJ ET 0.271 0.267 0.267 rg BT 504.673 638.299 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 510.094 638.299 Td /F1 9.8 Tf [(Michael S. )] TJ ET BT 26.250 626.394 Td /F1 9.8 Tf [(Levine)] TJ ET 0.271 0.267 0.267 rg BT 26.250 614.490 Td /F1 9.8 Tf [(Cepeda C, Cummings DM, Hickey MA, Kleiman-Weiner M, Chen J, Watson JB, Levine MS. Rescuing the Corticostriatal )] TJ ET BT 26.250 602.585 Td /F1 9.8 Tf [(Synaptic Disconnection in the R6/2 Mouse Model of Huntingtons Disease: Exercise, Adenosine Receptors and Ampakines. )] TJ ET BT 26.250 590.680 Td /F1 9.8 Tf [(PLOS Currents Huntington Disease. 2010 Sep 20 . Edition 1. doi: 10.1371/currents.RRN1182.)] TJ ET q 15.000 30.177 577.500 558.122 re W n 0.271 0.267 0.267 rg BT 26.250 561.578 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 541.623 Td /F1 9.8 Tf [(In the R6/2 mouse model of Huntingtons disease \(HD\) we examined the effects of a number of behavioral and pharmacological )] TJ ET BT 26.250 529.719 Td /F1 9.8 Tf [(manipulations aimed at rescuing the progressive loss of synaptic communication between cerebral cortex and striatum. Two )] TJ ET BT 26.250 517.814 Td /F1 9.8 Tf [(cohorts of transgenic mice with ~110 and 210 CAG repeats were utilized. Exercise prevented the reduction in striatal medium-)] TJ ET BT 26.250 505.909 Td /F1 9.8 Tf [(sized spiny neuron membrane capacitance but did not reestablish synaptic communication. Activation of adenosine A2A type )] TJ ET BT 26.250 494.004 Td /F1 9.8 Tf [(receptors renormalized postsynaptic activity to some extent. Finally, the ampakine Cx614, which has been shown to prevent ?-)] TJ ET BT 26.250 482.100 Td /F1 9.8 Tf [(amino-3-hydroxyl-5-methyl-4-isoxazole-propionate \(AMPA\) receptor desensitization, slow deactivation, and facilitate glutamate )] TJ ET BT 26.250 470.195 Td /F1 9.8 Tf [(release, induced significant increases in synaptic activity, albeit the effect was somewhat reduced in fully symptomatic, )] TJ ET BT 26.250 458.290 Td /F1 9.8 Tf [(compared to control mice. With some limitations, each of these strategies can be used to delay and partially rescue phenotypic )] TJ ET BT 26.250 446.385 Td /F1 9.8 Tf [(progression of HD in this model.)] TJ ET BT 26.250 409.783 Td /F4 12.0 Tf [(Funding Statement)] TJ ET BT 26.250 389.829 Td /F1 9.8 Tf [(This study was supported by grants from the USPHS \(NS41574\), the High Q Foundation, the Cure HD Initiative and the )] TJ ET BT 26.250 377.924 Td /F1 9.8 Tf [(Hereditary Disease Foundation.)] TJ ET BT 26.250 348.821 Td /F4 12.0 Tf [(Introduction)] TJ ET BT 26.250 328.867 Td /F1 9.8 Tf [(Huntingtons disease \(HD\) is an insidious, progressive and fatal neurodegenerative disorder caused by a mutation that expands )] TJ ET BT 26.250 316.962 Td /F1 9.8 Tf [(the number of CAG \(glutamine\) repeats )] TJ ET 0.267 0.267 0.267 rg BT 199.654 316.962 Td /F1 9.8 Tf [([1])] TJ ET 0.271 0.267 0.267 rg BT 210.496 316.962 Td /F1 9.8 Tf [( . Neuropathologically, HD is characterized by loss of striatal medium-sized spiny )] TJ ET BT 26.250 305.058 Td /F1 9.8 Tf [(neurons \(MSSNs\), as well as more discrete cell loss in other brain areas )] TJ ET 0.267 0.267 0.267 rg BT 340.512 305.058 Td /F1 9.8 Tf [([2])] TJ ET 0.271 0.267 0.267 rg BT 351.354 305.058 Td /F1 9.8 Tf [( . The symptoms include motor abnormalities, the )] TJ ET BT 26.250 293.153 Td /F1 9.8 Tf [(more prominent being chorea, as well as cognitive and psychiatric disturbances )] TJ ET 0.267 0.267 0.267 rg BT 371.429 293.153 Td /F1 9.8 Tf [([3])] TJ ET 0.271 0.267 0.267 rg BT 382.271 293.153 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 273.748 Td /F1 9.8 Tf [(Genetic mouse models of HD recapitulate some, but not all, of the phenotypic alterations found in human HD )] TJ ET 0.267 0.267 0.267 rg BT 497.721 273.748 Td /F1 9.8 Tf [([4])] TJ ET 0.271 0.267 0.267 rg BT 508.563 273.748 Td /F1 9.8 Tf [( . In particular, )] TJ ET BT 26.250 261.843 Td /F1 9.8 Tf [(the R6/2 model with ~150 CAG repeats has provided a wealth of information about mechanisms of disease progression and )] TJ ET BT 26.250 249.939 Td /F1 9.8 Tf [(represents a useful tool for drug screening as the progression of the phenotype occurs rapidly )] TJ ET 0.267 0.267 0.267 rg BT 432.698 249.939 Td /F1 9.8 Tf [([5])] TJ ET 0.271 0.267 0.267 rg BT 443.540 249.939 Td /F1 9.8 Tf [( and motor, histopathological, )] TJ ET BT 26.250 238.034 Td /F1 9.8 Tf [(and neuronal functional changes are reliable markers of the disease.)] TJ ET BT 26.250 218.629 Td /F1 9.8 Tf [(Our laboratory has characterized a number of morphological and electrophysiological alterations in striatum and cortex of these )] TJ ET BT 26.250 206.724 Td /F1 9.8 Tf [(mice )] TJ ET 0.267 0.267 0.267 rg BT 49.543 206.724 Td /F1 9.8 Tf [([6])] TJ ET BT 60.385 206.724 Td /F1 9.8 Tf [([7])] TJ ET 0.271 0.267 0.267 rg BT 71.227 206.724 Td /F1 9.8 Tf [( . We demonstrated reduced membrane capacitance and increased input resistance in neurons from symptomatic )] TJ ET BT 26.250 194.820 Td /F1 9.8 Tf [(R6/2 mice, along with decreases in somatic size, dendritic field, and number of spines of striatal MSSNs and cortical pyramidal )] TJ ET BT 26.250 182.915 Td /F1 9.8 Tf [(neurons )] TJ ET 0.267 0.267 0.267 rg BT 64.187 182.915 Td /F1 9.8 Tf [([8])] TJ ET 0.271 0.267 0.267 rg BT 75.029 182.915 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 163.510 Td /F1 9.8 Tf [(In addition, synaptic changes along the corticostriatal pathway occur )] TJ ET 0.267 0.267 0.267 rg BT 323.225 163.510 Td /F1 9.8 Tf [([8])] TJ ET BT 334.067 163.510 Td /F1 9.8 Tf [([9])] TJ ET BT 344.909 163.510 Td /F1 9.8 Tf [([10])] TJ ET 0.271 0.267 0.267 rg BT 361.172 163.510 Td /F1 9.8 Tf [( . An early and a late synaptic phenotype can be )] TJ ET BT 26.250 151.605 Td /F1 9.8 Tf [(characterized in striatal MSSNs. Early, synaptic dysregulation of glutamate release is manifested by the occurrence of large-)] TJ ET BT 26.250 139.701 Td /F1 9.8 Tf [(amplitude spontaneous excitatory postsynaptic currents \(EPSCs\) that reflect cortical hyperexcitability. Such increased )] TJ ET BT 26.250 127.796 Td /F1 9.8 Tf [(excitability could explain the propensity to seize and the lower convulsive threshold to systemic administration of epileptogenic )] TJ ET BT 26.250 115.891 Td /F1 9.8 Tf [(agents in R6/2 mice )] TJ ET 0.267 0.267 0.267 rg BT 115.121 115.891 Td /F1 9.8 Tf [([11])] TJ ET 0.271 0.267 0.267 rg BT 131.384 115.891 Td /F1 9.8 Tf [( . Large synaptic events in MSSNs can be reduced by riluzole and valproic acid )] TJ ET 0.267 0.267 0.267 rg BT 475.491 115.891 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 486.333 115.891 Td /F1 9.8 Tf [( and cortical )] TJ ET BT 26.250 103.986 Td /F1 9.8 Tf [(hyperexcitability can be renormalized by anticonvulsant agents such as rolipram and tiagabine )] TJ ET 0.267 0.267 0.267 rg BT 434.843 103.986 Td /F1 9.8 Tf [([12])] TJ ET BT 451.106 103.986 Td /F1 9.8 Tf [([13])] TJ ET 0.271 0.267 0.267 rg BT 467.369 103.986 Td /F1 9.8 Tf [( . Similarly, reducing )] TJ ET BT 26.250 92.082 Td /F1 9.8 Tf [(glutamatergic transmission by decortication around 4-6 weeks of age can be beneficial in R6/2 mice )] TJ ET 0.267 0.267 0.267 rg BT 458.682 92.082 Td /F1 9.8 Tf [([14])] TJ ET 0.271 0.267 0.267 rg BT 474.945 92.082 Td /F1 9.8 Tf [( . However, at about 5-)] TJ ET BT 26.250 80.177 Td /F1 9.8 Tf [(7 weeks of age, a progressive reduction in the frequency of spontaneous EPSCs in MSSNs occurs, leading to a virtual )] TJ ET BT 26.250 68.272 Td /F1 9.8 Tf [(disconnection between cortex and striatum )] TJ ET 0.267 0.267 0.267 rg BT 213.752 68.272 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 224.594 68.272 Td /F1 9.8 Tf [( . This disconnection is deleterious as it deprives the striatum of essential trophic )] TJ ET BT 26.250 56.367 Td /F1 9.8 Tf [(factors produced by cortical pyramidal neurons, such as brain-derived neurotrophic factor \(BDNF\), and could also result in a )] TJ ET BT 26.250 44.463 Td /F1 9.8 Tf [(deficit in survival signaling by synaptic N-methyl-D-aspartate \(NMDA\) receptors and preferential activation of proapoptotic )] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(1)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 8 0 obj << /Type /Font /Subtype /Type1 /Name /F1 /BaseFont /Helvetica /Encoding /WinAnsiEncoding >> endobj 9 0 obj << /Type /Font /Subtype /Type1 /Name /F2 /BaseFont /Times-Bold /Encoding /WinAnsiEncoding >> endobj 10 0 obj << /Type /Font /Subtype /Type1 /Name /F3 /BaseFont /Times-Italic /Encoding /WinAnsiEncoding >> endobj 11 0 obj << /Type /Font /Subtype /Type1 /Name /F4 /BaseFont /Helvetica-Bold /Encoding /WinAnsiEncoding >> endobj 12 0 obj << /Type /XObject /Subtype /Image /Width 500 /Height 52 /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 1 /Columns 500 /BitsPerComponent 8>> /ColorSpace /DeviceGray /BitsPerComponent 8 /Length 144>> stream x1 0 'ݲ؎"e{dzAdzAdzAdzAdzAdzAdzAdzAdzAdzAdzAdzAtlM0\ endstream endobj 13 0 obj << /Type /XObject /Subtype /Image /Width 500 /Height 52 /SMask 12 0 R /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 3 /Columns 500 /BitsPerComponent 8>> /ColorSpace /DeviceRGB /BitsPerComponent 8 /Length 4223>> stream xە8=,8C#h!hGv#0=j$q1uaNĥT*J&a_Zaa0 a0 a0 H^UUUUX!0 3SY|^G0 ÌÔ{]wa_>"OeYaG!8e}a6̖{4M&d:"qʲ\QUUMS<ϛNld2l6Z a<=2B(2vK7M\.GW0 rrWWavߖe9C?Eq8Gqy~~}_qdϽ(neYʒGjK4EQNjͷm{X?|7m۶mqP:Ȳp8Kmu]lNzuZ,NTeY"jlUUQW\,aRiVbȗLkHkEsjd.L6=Iו P]1t7Sc2uIuMM; K5>A$Ǒ$I׋nY 0_Hat;aq䃰U$nR ,zO7bT mhhԫܻu1F*qm'P}ܙ<ϕALO6Lw3nB.T4co{߽.lV $laԀIu!gwChxJ]Ne (+M"d-Eqc=P ! 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stream 0.271 0.267 0.267 rg q 15.000 35.206 577.500 741.794 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(extrasynaptic receptors )] TJ ET 0.267 0.267 0.267 rg BT 129.746 767.476 Td /F1 9.8 Tf [([15])] TJ ET BT 146.009 767.476 Td /F1 9.8 Tf [([16])] TJ ET BT 162.272 767.476 Td /F1 9.8 Tf [([17])] TJ ET BT 178.535 767.476 Td /F1 9.8 Tf [([18])] TJ ET 0.271 0.267 0.267 rg BT 194.798 767.476 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(As the progressive disconnection between cortex and striatum could explain many of the motor and cognitive symptoms, re-)] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(establishing normal connectivity \(i.e., increasing glutamatergic synaptic transmission\), may be helpful to ameliorate or reduce )] TJ ET BT 26.250 724.262 Td /F1 9.8 Tf [(progression of the disorder. The present series of studies used behavioral and pharmacological manipulations known to be )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(effective in slowing the progression of symptoms in HD and other neurodegenerative disorders, in attempts to slow or rescue )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(the late synaptic phenotype.)] TJ ET BT 26.250 681.048 Td /F1 9.8 Tf [(The beneficial effect of voluntary exercise in Parkinsons \(PD\) and Alzheimers \(AD\) diseases has been well documented )] TJ ET 0.267 0.267 0.267 rg BT 549.152 681.048 Td /F1 9.8 Tf [([19])] TJ ET 0.271 0.267 0.267 rg BT 565.415 681.048 Td /F1 9.8 Tf [( . )] TJ ET BT 26.250 669.143 Td /F1 9.8 Tf [(Exercise increases BDNF content and neurogenesis )] TJ ET 0.267 0.267 0.267 rg BT 254.927 669.143 Td /F1 9.8 Tf [([20])] TJ ET BT 271.190 669.143 Td /F1 9.8 Tf [([21])] TJ ET BT 287.452 669.143 Td /F1 9.8 Tf [([22])] TJ ET 0.271 0.267 0.267 rg BT 303.715 669.143 Td /F1 9.8 Tf [( , which could explain its benefits. However, there is little )] TJ ET BT 26.250 657.238 Td /F1 9.8 Tf [(information on the effects of exercise )] TJ ET BT 188.285 657.238 Td /F5 9.8 Tf [(per se)] TJ ET BT 215.380 657.238 Td /F1 9.8 Tf [( on the progression of symptoms of HD and, to our knowledge, no data on the )] TJ ET BT 26.250 645.333 Td /F1 9.8 Tf [(effects of exercise on synaptic activity in the corticostriatal pathway. Exercise may turn out to be beneficial, as in R6/1 mice, an )] TJ ET BT 26.250 633.429 Td /F1 9.8 Tf [(enriched environment delays the onset of the HD phenotype )] TJ ET 0.267 0.267 0.267 rg BT 288.554 633.429 Td /F1 9.8 Tf [([23])] TJ ET 0.271 0.267 0.267 rg BT 304.817 633.429 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 614.024 Td /F1 9.8 Tf [(We also targeted adenosine A)] TJ ET BT 156.861 611.960 Td /F1 8.7 Tf [(2A)] TJ ET BT 167.460 614.024 Td /F1 9.8 Tf [( receptors as there is evidence that their modulation can ameliorate symptoms of PD )] TJ ET 0.267 0.267 0.267 rg BT 534.860 614.024 Td /F1 9.8 Tf [([24])] TJ ET BT 551.123 614.024 Td /F1 9.8 Tf [([25])] TJ ET 0.271 0.267 0.267 rg BT 567.386 614.024 Td /F1 9.8 Tf [( . )] TJ ET BT 26.250 602.119 Td /F1 9.8 Tf [(In the R6/2 mouse, early changes in adenosine receptors and content occur and these changes could contribute to the HD )] TJ ET BT 26.250 590.214 Td /F1 9.8 Tf [(phenotype )] TJ ET 0.267 0.267 0.267 rg BT 74.493 590.214 Td /F1 9.8 Tf [([26])] TJ ET 0.271 0.267 0.267 rg BT 90.756 590.214 Td /F1 9.8 Tf [( . In addition, recent studies indicate that adenosine receptor agonists differentially modulate NMDA receptor-)] TJ ET BT 26.250 578.310 Td /F1 9.8 Tf [(mediated excitotoxicity in R6/2 mice )] TJ ET 0.267 0.267 0.267 rg BT 183.927 578.310 Td /F1 9.8 Tf [([27])] TJ ET 0.271 0.267 0.267 rg BT 200.190 578.310 Td /F1 9.8 Tf [( and both A)] TJ ET BT 250.061 576.245 Td /F1 8.7 Tf [(2A)] TJ ET BT 260.661 578.310 Td /F1 9.8 Tf [( receptor agonists and antagonists can be used to treat HD symptoms )] TJ ET 0.267 0.267 0.267 rg BT 26.250 566.405 Td /F1 9.8 Tf [([28])] TJ ET BT 42.513 566.405 Td /F1 9.8 Tf [([29])] TJ ET 0.271 0.267 0.267 rg BT 58.776 566.405 Td /F1 9.8 Tf [( . However, little is known about the cellular mechanisms underlying A)] TJ ET BT 360.051 564.341 Td /F1 8.7 Tf [(2A)] TJ ET BT 370.650 566.405 Td /F1 9.8 Tf [( receptor dysfunction in HD. Thus, we examined )] TJ ET BT 26.250 554.500 Td /F1 9.8 Tf [(the effects of A)] TJ ET BT 91.292 552.436 Td /F1 8.7 Tf [(2A)] TJ ET BT 101.892 554.500 Td /F1 9.8 Tf [( receptor modulators on spontaneous glutamate synaptic currents.)] TJ ET BT 26.250 535.095 Td /F1 9.8 Tf [(Finally the ampakines, drugs that slow deactivation of a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate \(AMPA\) glutamate )] TJ ET BT 26.250 523.191 Td /F1 9.8 Tf [(receptors )] TJ ET 0.267 0.267 0.267 rg BT 69.599 523.191 Td /F1 9.8 Tf [([30])] TJ ET 0.271 0.267 0.267 rg BT 85.862 523.191 Td /F1 9.8 Tf [( , have been suggested as potential therapeutic targets in a number of neurological disorders )] TJ ET 0.267 0.267 0.267 rg BT 489.073 523.191 Td /F1 9.8 Tf [([31])] TJ ET 0.271 0.267 0.267 rg BT 505.336 523.191 Td /F1 9.8 Tf [( . We tested )] TJ ET BT 26.250 511.286 Td /F1 9.8 Tf [(Cx614, as this compound has been shown to increase BDNF production )] TJ ET 0.267 0.267 0.267 rg BT 340.561 511.286 Td /F1 9.8 Tf [([32])] TJ ET 0.271 0.267 0.267 rg BT 356.824 511.286 Td /F1 9.8 Tf [( and BDNF rescues synaptic deficits in the )] TJ ET BT 26.250 499.381 Td /F1 9.8 Tf [(hippocampus of a knock-in mouse model of HD )] TJ ET 0.267 0.267 0.267 rg BT 233.788 499.381 Td /F1 9.8 Tf [([33])] TJ ET 0.271 0.267 0.267 rg BT 250.052 499.381 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 462.779 Td /F4 12.0 Tf [(Methods)] TJ ET BT 26.250 442.824 Td /F1 9.8 Tf [(All experimental procedures were performed in accordance with the United States Public Health Service )] TJ ET BT 477.090 442.824 Td /F5 9.8 Tf [(Guide for Care and )] TJ ET BT 26.250 430.920 Td /F5 9.8 Tf [(Use of Laboratory Animals)] TJ ET BT 141.125 430.920 Td /F1 9.8 Tf [( and were approved by the Institutional AnimalCare and Use Committee at the University of )] TJ ET BT 26.250 419.015 Td /F1 9.8 Tf [(California, Los Angeles \(UCLA\).)] TJ ET BT 26.250 399.610 Td /F4 9.8 Tf [(Mice, Ages and Treatments:)] TJ ET BT 26.250 380.205 Td /F1 9.8 Tf [(R6/2 transgenic mice and wildtype \(WT\) littermates were obtained from our colony at UCLA. All animals were genotyped twice, )] TJ ET BT 26.250 368.301 Td /F1 9.8 Tf [(once after weaning and again after the electrophysiological recordings. In transgenic mice the number of CAG repeats also was )] TJ ET BT 26.250 356.396 Td /F1 9.8 Tf [(measured. Mice for the exercise study had 106-114 CAG repeats, while mice for the adenosine receptor study had 200-220 )] TJ ET BT 26.250 344.491 Td /F1 9.8 Tf [(CAG repeats. Mice used for the ampakine study had 106-121 CAG repeats.)] TJ ET BT 26.250 325.086 Td /F4 9.8 Tf [(Voluntary Exercise:)] TJ ET BT 26.250 305.682 Td /F1 9.8 Tf [(Four groups of mice \(including both males and females\) were examined. Two groups of WT and R6/2 mice \(aged 3 weeks, n=9 )] TJ ET BT 26.250 293.777 Td /F1 9.8 Tf [(in each group\) were placed in individual cages equipped with a running wheel as previously described )] TJ ET 0.267 0.267 0.267 rg BT 467.906 293.777 Td /F1 9.8 Tf [([34])] TJ ET BT 484.168 293.777 Td /F1 9.8 Tf [([35])] TJ ET 0.271 0.267 0.267 rg BT 500.431 293.777 Td /F1 9.8 Tf [( . Two other )] TJ ET BT 26.250 281.872 Td /F1 9.8 Tf [(groups of WT and R6/2 littermate mice \(n=9 in each group\) were placed in individual cages with running wheels but these were )] TJ ET BT 26.250 269.967 Td /F1 9.8 Tf [(fixed and immobile. Briefly, for running behavior, cages were equipped with a running wheel \(23 cm diameter, Mini Mitter )] TJ ET BT 26.250 258.063 Td /F1 9.8 Tf [(Company Inc., Bend OR\) and rotations of the wheel were detected and recorded in 3 min bin intervals \(VitalView Data )] TJ ET BT 26.250 246.158 Td /F1 9.8 Tf [(Acquisition Software V 4.0, Mini Mitter Company Inc., Bend OR\). Wheel running activity during light and dark phases was )] TJ ET BT 26.250 234.253 Td /F1 9.8 Tf [(calculated subsequently \(ActiView, V 1.2, Mini Mitter Company Inc., Bend OR\). After 3-6 weeks in the cages mice were )] TJ ET BT 26.250 222.348 Td /F1 9.8 Tf [(sacrificed for slice electrophysiology and BDNF measurements. However, 3 animals \(one WT and two transgenic\) died and )] TJ ET BT 26.250 210.444 Td /F1 9.8 Tf [(were not used for electrophysiological recordings.)] TJ ET BT 26.250 191.039 Td /F4 9.8 Tf [(BDNF Determination)] TJ ET BT 121.585 191.039 Td /F1 9.8 Tf [( :)] TJ ET BT 26.250 171.634 Td /F1 9.8 Tf [(We used the BDNF E)] TJ ET BT 119.450 169.570 Td /F1 8.7 Tf [(max)] TJ ET BT 135.822 175.522 Td /F1 8.7 Tf [()] TJ ET BT 142.209 171.634 Td /F1 9.8 Tf [( Immunoassay System from Promega to quantify BDNF by ELISA in mouse striatum obtained from )] TJ ET BT 26.250 159.729 Td /F1 9.8 Tf [(the same groups of WT and R6/2 mice either with or without running wheel as exercise. The striatum was dissected out, flash )] TJ ET BT 26.250 147.825 Td /F1 9.8 Tf [(frozen on dry ice and stored at -80 )] TJ ET BT 177.453 151.713 Td /F1 8.7 Tf [(o)] TJ ET BT 182.272 147.825 Td /F1 9.8 Tf [( C until assayed. Prior to each assay, the striatum was homogenized in lysis buffer \(137mM )] TJ ET BT 26.250 135.920 Td /F1 9.8 Tf [(NaCl, 20mM Tris-HCL at pH 8, 1% NP40, 10% glycerol, 1mM PMSF, 10g/ml aprotinin, 1g/ml leupeptin, 0.5mM sodium )] TJ ET BT 26.250 124.015 Td /F1 9.8 Tf [(vanadate\) by combined douncing and sonication followed by microcentrifugation at 16,000 g. The supernatant fraction was )] TJ ET BT 26.250 112.110 Td /F1 9.8 Tf [(saved for ELISA and its protein concentration was determined by the Bradford method )] TJ ET 0.267 0.267 0.267 rg BT 400.728 112.110 Td /F1 9.8 Tf [([36])] TJ ET 0.271 0.267 0.267 rg BT 416.991 112.110 Td /F1 9.8 Tf [( . A standard BDNF sample and )] TJ ET BT 26.250 100.206 Td /F1 9.8 Tf [(multiple striatal supernatant samples were serially diluted in duplicate in 96-well plates and the ELISA was carried out using a )] TJ ET BT 26.250 88.301 Td /F1 9.8 Tf [(combination of monoclonal and polyclonal antibodies to BDNF. Striatal BDNF values were determined by comparison to a )] TJ ET BT 26.250 76.396 Td /F1 9.8 Tf [(BDNF Standard curve \(0-500 pg/ml\). Final BDNF concentrations in striatal supernatants were calculated as pg/g total striatal )] TJ ET BT 26.250 64.491 Td /F1 9.8 Tf [(protein.)] TJ ET Q q 15.000 35.206 577.500 741.794 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(extrasynaptic receptors )] TJ ET 0.267 0.267 0.267 rg BT 129.746 767.476 Td /F1 9.8 Tf [([15])] TJ ET BT 146.009 767.476 Td /F1 9.8 Tf [([16])] TJ ET BT 162.272 767.476 Td /F1 9.8 Tf [([17])] TJ ET BT 178.535 767.476 Td /F1 9.8 Tf [([18])] TJ ET 0.271 0.267 0.267 rg BT 194.798 767.476 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(As the progressive disconnection between cortex and striatum could explain many of the motor and cognitive symptoms, re-)] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(establishing normal connectivity \(i.e., increasing glutamatergic synaptic transmission\), may be helpful to ameliorate or reduce )] TJ ET BT 26.250 724.262 Td /F1 9.8 Tf [(progression of the disorder. The present series of studies used behavioral and pharmacological manipulations known to be )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(effective in slowing the progression of symptoms in HD and other neurodegenerative disorders, in attempts to slow or rescue )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(the late synaptic phenotype.)] TJ ET BT 26.250 681.048 Td /F1 9.8 Tf [(The beneficial effect of voluntary exercise in Parkinsons \(PD\) and Alzheimers \(AD\) diseases has been well documented )] TJ ET 0.267 0.267 0.267 rg BT 549.152 681.048 Td /F1 9.8 Tf [([19])] TJ ET 0.271 0.267 0.267 rg BT 565.415 681.048 Td /F1 9.8 Tf [( . )] TJ ET BT 26.250 669.143 Td /F1 9.8 Tf [(Exercise increases BDNF content and neurogenesis )] TJ ET 0.267 0.267 0.267 rg BT 254.927 669.143 Td /F1 9.8 Tf [([20])] TJ ET BT 271.190 669.143 Td /F1 9.8 Tf [([21])] TJ ET BT 287.452 669.143 Td /F1 9.8 Tf [([22])] TJ ET 0.271 0.267 0.267 rg BT 303.715 669.143 Td /F1 9.8 Tf [( , which could explain its benefits. However, there is little )] TJ ET BT 26.250 657.238 Td /F1 9.8 Tf [(information on the effects of exercise )] TJ ET BT 188.285 657.238 Td /F5 9.8 Tf [(per se)] TJ ET BT 215.380 657.238 Td /F1 9.8 Tf [( on the progression of symptoms of HD and, to our knowledge, no data on the )] TJ ET BT 26.250 645.333 Td /F1 9.8 Tf [(effects of exercise on synaptic activity in the corticostriatal pathway. Exercise may turn out to be beneficial, as in R6/1 mice, an )] TJ ET BT 26.250 633.429 Td /F1 9.8 Tf [(enriched environment delays the onset of the HD phenotype )] TJ ET 0.267 0.267 0.267 rg BT 288.554 633.429 Td /F1 9.8 Tf [([23])] TJ ET 0.271 0.267 0.267 rg BT 304.817 633.429 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 614.024 Td /F1 9.8 Tf [(We also targeted adenosine A)] TJ ET BT 156.861 611.960 Td /F1 8.7 Tf [(2A)] TJ ET BT 167.460 614.024 Td /F1 9.8 Tf [( receptors as there is evidence that their modulation can ameliorate symptoms of PD )] TJ ET 0.267 0.267 0.267 rg BT 534.860 614.024 Td /F1 9.8 Tf [([24])] TJ ET BT 551.123 614.024 Td /F1 9.8 Tf [([25])] TJ ET 0.271 0.267 0.267 rg BT 567.386 614.024 Td /F1 9.8 Tf [( . )] TJ ET BT 26.250 602.119 Td /F1 9.8 Tf [(In the R6/2 mouse, early changes in adenosine receptors and content occur and these changes could contribute to the HD )] TJ ET BT 26.250 590.214 Td /F1 9.8 Tf [(phenotype )] TJ ET 0.267 0.267 0.267 rg BT 74.493 590.214 Td /F1 9.8 Tf [([26])] TJ ET 0.271 0.267 0.267 rg BT 90.756 590.214 Td /F1 9.8 Tf [( . In addition, recent studies indicate that adenosine receptor agonists differentially modulate NMDA receptor-)] TJ ET BT 26.250 578.310 Td /F1 9.8 Tf [(mediated excitotoxicity in R6/2 mice )] TJ ET 0.267 0.267 0.267 rg BT 183.927 578.310 Td /F1 9.8 Tf [([27])] TJ ET 0.271 0.267 0.267 rg BT 200.190 578.310 Td /F1 9.8 Tf [( and both A)] TJ ET BT 250.061 576.245 Td /F1 8.7 Tf [(2A)] TJ ET BT 260.661 578.310 Td /F1 9.8 Tf [( receptor agonists and antagonists can be used to treat HD symptoms )] TJ ET 0.267 0.267 0.267 rg BT 26.250 566.405 Td /F1 9.8 Tf [([28])] TJ ET BT 42.513 566.405 Td /F1 9.8 Tf [([29])] TJ ET 0.271 0.267 0.267 rg BT 58.776 566.405 Td /F1 9.8 Tf [( . However, little is known about the cellular mechanisms underlying A)] TJ ET BT 360.051 564.341 Td /F1 8.7 Tf [(2A)] TJ ET BT 370.650 566.405 Td /F1 9.8 Tf [( receptor dysfunction in HD. Thus, we examined )] TJ ET BT 26.250 554.500 Td /F1 9.8 Tf [(the effects of A)] TJ ET BT 91.292 552.436 Td /F1 8.7 Tf [(2A)] TJ ET BT 101.892 554.500 Td /F1 9.8 Tf [( receptor modulators on spontaneous glutamate synaptic currents.)] TJ ET BT 26.250 535.095 Td /F1 9.8 Tf [(Finally the ampakines, drugs that slow deactivation of a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate \(AMPA\) glutamate )] TJ ET BT 26.250 523.191 Td /F1 9.8 Tf [(receptors )] TJ ET 0.267 0.267 0.267 rg BT 69.599 523.191 Td /F1 9.8 Tf [([30])] TJ ET 0.271 0.267 0.267 rg BT 85.862 523.191 Td /F1 9.8 Tf [( , have been suggested as potential therapeutic targets in a number of neurological disorders )] TJ ET 0.267 0.267 0.267 rg BT 489.073 523.191 Td /F1 9.8 Tf [([31])] TJ ET 0.271 0.267 0.267 rg BT 505.336 523.191 Td /F1 9.8 Tf [( . We tested )] TJ ET BT 26.250 511.286 Td /F1 9.8 Tf [(Cx614, as this compound has been shown to increase BDNF production )] TJ ET 0.267 0.267 0.267 rg BT 340.561 511.286 Td /F1 9.8 Tf [([32])] TJ ET 0.271 0.267 0.267 rg BT 356.824 511.286 Td /F1 9.8 Tf [( and BDNF rescues synaptic deficits in the )] TJ ET BT 26.250 499.381 Td /F1 9.8 Tf [(hippocampus of a knock-in mouse model of HD )] TJ ET 0.267 0.267 0.267 rg BT 233.788 499.381 Td /F1 9.8 Tf [([33])] TJ ET 0.271 0.267 0.267 rg BT 250.052 499.381 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 462.779 Td /F4 12.0 Tf [(Methods)] TJ ET BT 26.250 442.824 Td /F1 9.8 Tf [(All experimental procedures were performed in accordance with the United States Public Health Service )] TJ ET BT 477.090 442.824 Td /F5 9.8 Tf [(Guide for Care and )] TJ ET BT 26.250 430.920 Td /F5 9.8 Tf [(Use of Laboratory Animals)] TJ ET BT 141.125 430.920 Td /F1 9.8 Tf [( and were approved by the Institutional AnimalCare and Use Committee at the University of )] TJ ET BT 26.250 419.015 Td /F1 9.8 Tf [(California, Los Angeles \(UCLA\).)] TJ ET BT 26.250 399.610 Td /F4 9.8 Tf [(Mice, Ages and Treatments:)] TJ ET BT 26.250 380.205 Td /F1 9.8 Tf [(R6/2 transgenic mice and wildtype \(WT\) littermates were obtained from our colony at UCLA. All animals were genotyped twice, )] TJ ET BT 26.250 368.301 Td /F1 9.8 Tf [(once after weaning and again after the electrophysiological recordings. In transgenic mice the number of CAG repeats also was )] TJ ET BT 26.250 356.396 Td /F1 9.8 Tf [(measured. Mice for the exercise study had 106-114 CAG repeats, while mice for the adenosine receptor study had 200-220 )] TJ ET BT 26.250 344.491 Td /F1 9.8 Tf [(CAG repeats. Mice used for the ampakine study had 106-121 CAG repeats.)] TJ ET BT 26.250 325.086 Td /F4 9.8 Tf [(Voluntary Exercise:)] TJ ET BT 26.250 305.682 Td /F1 9.8 Tf [(Four groups of mice \(including both males and females\) were examined. Two groups of WT and R6/2 mice \(aged 3 weeks, n=9 )] TJ ET BT 26.250 293.777 Td /F1 9.8 Tf [(in each group\) were placed in individual cages equipped with a running wheel as previously described )] TJ ET 0.267 0.267 0.267 rg BT 467.906 293.777 Td /F1 9.8 Tf [([34])] TJ ET BT 484.168 293.777 Td /F1 9.8 Tf [([35])] TJ ET 0.271 0.267 0.267 rg BT 500.431 293.777 Td /F1 9.8 Tf [( . Two other )] TJ ET BT 26.250 281.872 Td /F1 9.8 Tf [(groups of WT and R6/2 littermate mice \(n=9 in each group\) were placed in individual cages with running wheels but these were )] TJ ET BT 26.250 269.967 Td /F1 9.8 Tf [(fixed and immobile. Briefly, for running behavior, cages were equipped with a running wheel \(23 cm diameter, Mini Mitter )] TJ ET BT 26.250 258.063 Td /F1 9.8 Tf [(Company Inc., Bend OR\) and rotations of the wheel were detected and recorded in 3 min bin intervals \(VitalView Data )] TJ ET BT 26.250 246.158 Td /F1 9.8 Tf [(Acquisition Software V 4.0, Mini Mitter Company Inc., Bend OR\). Wheel running activity during light and dark phases was )] TJ ET BT 26.250 234.253 Td /F1 9.8 Tf [(calculated subsequently \(ActiView, V 1.2, Mini Mitter Company Inc., Bend OR\). After 3-6 weeks in the cages mice were )] TJ ET BT 26.250 222.348 Td /F1 9.8 Tf [(sacrificed for slice electrophysiology and BDNF measurements. However, 3 animals \(one WT and two transgenic\) died and )] TJ ET BT 26.250 210.444 Td /F1 9.8 Tf [(were not used for electrophysiological recordings.)] TJ ET BT 26.250 191.039 Td /F4 9.8 Tf [(BDNF Determination)] TJ ET BT 121.585 191.039 Td /F1 9.8 Tf [( :)] TJ ET BT 26.250 171.634 Td /F1 9.8 Tf [(We used the BDNF E)] TJ ET BT 119.450 169.570 Td /F1 8.7 Tf [(max)] TJ ET BT 135.822 175.522 Td /F1 8.7 Tf [()] TJ ET BT 142.209 171.634 Td /F1 9.8 Tf [( Immunoassay System from Promega to quantify BDNF by ELISA in mouse striatum obtained from )] TJ ET BT 26.250 159.729 Td /F1 9.8 Tf [(the same groups of WT and R6/2 mice either with or without running wheel as exercise. The striatum was dissected out, flash )] TJ ET BT 26.250 147.825 Td /F1 9.8 Tf [(frozen on dry ice and stored at -80 )] TJ ET BT 177.453 151.713 Td /F1 8.7 Tf [(o)] TJ ET BT 182.272 147.825 Td /F1 9.8 Tf [( C until assayed. Prior to each assay, the striatum was homogenized in lysis buffer \(137mM )] TJ ET BT 26.250 135.920 Td /F1 9.8 Tf [(NaCl, 20mM Tris-HCL at pH 8, 1% NP40, 10% glycerol, 1mM PMSF, 10g/ml aprotinin, 1g/ml leupeptin, 0.5mM sodium )] TJ ET BT 26.250 124.015 Td /F1 9.8 Tf [(vanadate\) by combined douncing and sonication followed by microcentrifugation at 16,000 g. The supernatant fraction was )] TJ ET BT 26.250 112.110 Td /F1 9.8 Tf [(saved for ELISA and its protein concentration was determined by the Bradford method )] TJ ET 0.267 0.267 0.267 rg BT 400.728 112.110 Td /F1 9.8 Tf [([36])] TJ ET 0.271 0.267 0.267 rg BT 416.991 112.110 Td /F1 9.8 Tf [( . A standard BDNF sample and )] TJ ET BT 26.250 100.206 Td /F1 9.8 Tf [(multiple striatal supernatant samples were serially diluted in duplicate in 96-well plates and the ELISA was carried out using a )] TJ ET BT 26.250 88.301 Td /F1 9.8 Tf [(combination of monoclonal and polyclonal antibodies to BDNF. Striatal BDNF values were determined by comparison to a )] TJ ET BT 26.250 76.396 Td /F1 9.8 Tf [(BDNF Standard curve \(0-500 pg/ml\). Final BDNF concentrations in striatal supernatants were calculated as pg/g total striatal )] TJ ET BT 26.250 64.491 Td /F1 9.8 Tf [(protein.)] TJ ET Q q 15.000 35.206 577.500 741.794 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(extrasynaptic receptors )] TJ ET 0.267 0.267 0.267 rg BT 129.746 767.476 Td /F1 9.8 Tf [([15])] TJ ET BT 146.009 767.476 Td /F1 9.8 Tf [([16])] TJ ET BT 162.272 767.476 Td /F1 9.8 Tf [([17])] TJ ET BT 178.535 767.476 Td /F1 9.8 Tf [([18])] TJ ET 0.271 0.267 0.267 rg BT 194.798 767.476 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(As the progressive disconnection between cortex and striatum could explain many of the motor and cognitive symptoms, re-)] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(establishing normal connectivity \(i.e., increasing glutamatergic synaptic transmission\), may be helpful to ameliorate or reduce )] TJ ET BT 26.250 724.262 Td /F1 9.8 Tf [(progression of the disorder. The present series of studies used behavioral and pharmacological manipulations known to be )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(effective in slowing the progression of symptoms in HD and other neurodegenerative disorders, in attempts to slow or rescue )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(the late synaptic phenotype.)] TJ ET BT 26.250 681.048 Td /F1 9.8 Tf [(The beneficial effect of voluntary exercise in Parkinsons \(PD\) and Alzheimers \(AD\) diseases has been well documented )] TJ ET 0.267 0.267 0.267 rg BT 549.152 681.048 Td /F1 9.8 Tf [([19])] TJ ET 0.271 0.267 0.267 rg BT 565.415 681.048 Td /F1 9.8 Tf [( . )] TJ ET BT 26.250 669.143 Td /F1 9.8 Tf [(Exercise increases BDNF content and neurogenesis )] TJ ET 0.267 0.267 0.267 rg BT 254.927 669.143 Td /F1 9.8 Tf [([20])] TJ ET BT 271.190 669.143 Td /F1 9.8 Tf [([21])] TJ ET BT 287.452 669.143 Td /F1 9.8 Tf [([22])] TJ ET 0.271 0.267 0.267 rg BT 303.715 669.143 Td /F1 9.8 Tf [( , which could explain its benefits. However, there is little )] TJ ET BT 26.250 657.238 Td /F1 9.8 Tf [(information on the effects of exercise )] TJ ET BT 188.285 657.238 Td /F5 9.8 Tf [(per se)] TJ ET BT 215.380 657.238 Td /F1 9.8 Tf [( on the progression of symptoms of HD and, to our knowledge, no data on the )] TJ ET BT 26.250 645.333 Td /F1 9.8 Tf [(effects of exercise on synaptic activity in the corticostriatal pathway. Exercise may turn out to be beneficial, as in R6/1 mice, an )] TJ ET BT 26.250 633.429 Td /F1 9.8 Tf [(enriched environment delays the onset of the HD phenotype )] TJ ET 0.267 0.267 0.267 rg BT 288.554 633.429 Td /F1 9.8 Tf [([23])] TJ ET 0.271 0.267 0.267 rg BT 304.817 633.429 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 614.024 Td /F1 9.8 Tf [(We also targeted adenosine A)] TJ ET BT 156.861 611.960 Td /F1 8.7 Tf [(2A)] TJ ET BT 167.460 614.024 Td /F1 9.8 Tf [( receptors as there is evidence that their modulation can ameliorate symptoms of PD )] TJ ET 0.267 0.267 0.267 rg BT 534.860 614.024 Td /F1 9.8 Tf [([24])] TJ ET BT 551.123 614.024 Td /F1 9.8 Tf [([25])] TJ ET 0.271 0.267 0.267 rg BT 567.386 614.024 Td /F1 9.8 Tf [( . )] TJ ET BT 26.250 602.119 Td /F1 9.8 Tf [(In the R6/2 mouse, early changes in adenosine receptors and content occur and these changes could contribute to the HD )] TJ ET BT 26.250 590.214 Td /F1 9.8 Tf [(phenotype )] TJ ET 0.267 0.267 0.267 rg BT 74.493 590.214 Td /F1 9.8 Tf [([26])] TJ ET 0.271 0.267 0.267 rg BT 90.756 590.214 Td /F1 9.8 Tf [( . In addition, recent studies indicate that adenosine receptor agonists differentially modulate NMDA receptor-)] TJ ET BT 26.250 578.310 Td /F1 9.8 Tf [(mediated excitotoxicity in R6/2 mice )] TJ ET 0.267 0.267 0.267 rg BT 183.927 578.310 Td /F1 9.8 Tf [([27])] TJ ET 0.271 0.267 0.267 rg BT 200.190 578.310 Td /F1 9.8 Tf [( and both A)] TJ ET BT 250.061 576.245 Td /F1 8.7 Tf [(2A)] TJ ET BT 260.661 578.310 Td /F1 9.8 Tf [( receptor agonists and antagonists can be used to treat HD symptoms )] TJ ET 0.267 0.267 0.267 rg BT 26.250 566.405 Td /F1 9.8 Tf [([28])] TJ ET BT 42.513 566.405 Td /F1 9.8 Tf [([29])] TJ ET 0.271 0.267 0.267 rg BT 58.776 566.405 Td /F1 9.8 Tf [( . However, little is known about the cellular mechanisms underlying A)] TJ ET BT 360.051 564.341 Td /F1 8.7 Tf [(2A)] TJ ET BT 370.650 566.405 Td /F1 9.8 Tf [( receptor dysfunction in HD. Thus, we examined )] TJ ET BT 26.250 554.500 Td /F1 9.8 Tf [(the effects of A)] TJ ET BT 91.292 552.436 Td /F1 8.7 Tf [(2A)] TJ ET BT 101.892 554.500 Td /F1 9.8 Tf [( receptor modulators on spontaneous glutamate synaptic currents.)] TJ ET BT 26.250 535.095 Td /F1 9.8 Tf [(Finally the ampakines, drugs that slow deactivation of a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate \(AMPA\) glutamate )] TJ ET BT 26.250 523.191 Td /F1 9.8 Tf [(receptors )] TJ ET 0.267 0.267 0.267 rg BT 69.599 523.191 Td /F1 9.8 Tf [([30])] TJ ET 0.271 0.267 0.267 rg BT 85.862 523.191 Td /F1 9.8 Tf [( , have been suggested as potential therapeutic targets in a number of neurological disorders )] TJ ET 0.267 0.267 0.267 rg BT 489.073 523.191 Td /F1 9.8 Tf [([31])] TJ ET 0.271 0.267 0.267 rg BT 505.336 523.191 Td /F1 9.8 Tf [( . We tested )] TJ ET BT 26.250 511.286 Td /F1 9.8 Tf [(Cx614, as this compound has been shown to increase BDNF production )] TJ ET 0.267 0.267 0.267 rg BT 340.561 511.286 Td /F1 9.8 Tf [([32])] TJ ET 0.271 0.267 0.267 rg BT 356.824 511.286 Td /F1 9.8 Tf [( and BDNF rescues synaptic deficits in the )] TJ ET BT 26.250 499.381 Td /F1 9.8 Tf [(hippocampus of a knock-in mouse model of HD )] TJ ET 0.267 0.267 0.267 rg BT 233.788 499.381 Td /F1 9.8 Tf [([33])] TJ ET 0.271 0.267 0.267 rg BT 250.052 499.381 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 462.779 Td /F4 12.0 Tf [(Methods)] TJ ET BT 26.250 442.824 Td /F1 9.8 Tf [(All experimental procedures were performed in accordance with the United States Public Health Service )] TJ ET BT 477.090 442.824 Td /F5 9.8 Tf [(Guide for Care and )] TJ ET BT 26.250 430.920 Td /F5 9.8 Tf [(Use of Laboratory Animals)] TJ ET BT 141.125 430.920 Td /F1 9.8 Tf [( and were approved by the Institutional AnimalCare and Use Committee at the University of )] TJ ET BT 26.250 419.015 Td /F1 9.8 Tf [(California, Los Angeles \(UCLA\).)] TJ ET BT 26.250 399.610 Td /F4 9.8 Tf [(Mice, Ages and Treatments:)] TJ ET BT 26.250 380.205 Td /F1 9.8 Tf [(R6/2 transgenic mice and wildtype \(WT\) littermates were obtained from our colony at UCLA. All animals were genotyped twice, )] TJ ET BT 26.250 368.301 Td /F1 9.8 Tf [(once after weaning and again after the electrophysiological recordings. In transgenic mice the number of CAG repeats also was )] TJ ET BT 26.250 356.396 Td /F1 9.8 Tf [(measured. Mice for the exercise study had 106-114 CAG repeats, while mice for the adenosine receptor study had 200-220 )] TJ ET BT 26.250 344.491 Td /F1 9.8 Tf [(CAG repeats. Mice used for the ampakine study had 106-121 CAG repeats.)] TJ ET BT 26.250 325.086 Td /F4 9.8 Tf [(Voluntary Exercise:)] TJ ET BT 26.250 305.682 Td /F1 9.8 Tf [(Four groups of mice \(including both males and females\) were examined. Two groups of WT and R6/2 mice \(aged 3 weeks, n=9 )] TJ ET BT 26.250 293.777 Td /F1 9.8 Tf [(in each group\) were placed in individual cages equipped with a running wheel as previously described )] TJ ET 0.267 0.267 0.267 rg BT 467.906 293.777 Td /F1 9.8 Tf [([34])] TJ ET BT 484.168 293.777 Td /F1 9.8 Tf [([35])] TJ ET 0.271 0.267 0.267 rg BT 500.431 293.777 Td /F1 9.8 Tf [( . Two other )] TJ ET BT 26.250 281.872 Td /F1 9.8 Tf [(groups of WT and R6/2 littermate mice \(n=9 in each group\) were placed in individual cages with running wheels but these were )] TJ ET BT 26.250 269.967 Td /F1 9.8 Tf [(fixed and immobile. Briefly, for running behavior, cages were equipped with a running wheel \(23 cm diameter, Mini Mitter )] TJ ET BT 26.250 258.063 Td /F1 9.8 Tf [(Company Inc., Bend OR\) and rotations of the wheel were detected and recorded in 3 min bin intervals \(VitalView Data )] TJ ET BT 26.250 246.158 Td /F1 9.8 Tf [(Acquisition Software V 4.0, Mini Mitter Company Inc., Bend OR\). Wheel running activity during light and dark phases was )] TJ ET BT 26.250 234.253 Td /F1 9.8 Tf [(calculated subsequently \(ActiView, V 1.2, Mini Mitter Company Inc., Bend OR\). After 3-6 weeks in the cages mice were )] TJ ET BT 26.250 222.348 Td /F1 9.8 Tf [(sacrificed for slice electrophysiology and BDNF measurements. However, 3 animals \(one WT and two transgenic\) died and )] TJ ET BT 26.250 210.444 Td /F1 9.8 Tf [(were not used for electrophysiological recordings.)] TJ ET BT 26.250 191.039 Td /F4 9.8 Tf [(BDNF Determination)] TJ ET BT 121.585 191.039 Td /F1 9.8 Tf [( :)] TJ ET BT 26.250 171.634 Td /F1 9.8 Tf [(We used the BDNF E)] TJ ET BT 119.450 169.570 Td /F1 8.7 Tf [(max)] TJ ET BT 135.822 175.522 Td /F1 8.7 Tf [()] TJ ET BT 142.209 171.634 Td /F1 9.8 Tf [( Immunoassay System from Promega to quantify BDNF by ELISA in mouse striatum obtained from )] TJ ET BT 26.250 159.729 Td /F1 9.8 Tf [(the same groups of WT and R6/2 mice either with or without running wheel as exercise. The striatum was dissected out, flash )] TJ ET BT 26.250 147.825 Td /F1 9.8 Tf [(frozen on dry ice and stored at -80 )] TJ ET BT 177.453 151.713 Td /F1 8.7 Tf [(o)] TJ ET BT 182.272 147.825 Td /F1 9.8 Tf [( C until assayed. Prior to each assay, the striatum was homogenized in lysis buffer \(137mM )] TJ ET BT 26.250 135.920 Td /F1 9.8 Tf [(NaCl, 20mM Tris-HCL at pH 8, 1% NP40, 10% glycerol, 1mM PMSF, 10g/ml aprotinin, 1g/ml leupeptin, 0.5mM sodium )] TJ ET BT 26.250 124.015 Td /F1 9.8 Tf [(vanadate\) by combined douncing and sonication followed by microcentrifugation at 16,000 g. The supernatant fraction was )] TJ ET BT 26.250 112.110 Td /F1 9.8 Tf [(saved for ELISA and its protein concentration was determined by the Bradford method )] TJ ET 0.267 0.267 0.267 rg BT 400.728 112.110 Td /F1 9.8 Tf [([36])] TJ ET 0.271 0.267 0.267 rg BT 416.991 112.110 Td /F1 9.8 Tf [( . A standard BDNF sample and )] TJ ET BT 26.250 100.206 Td /F1 9.8 Tf [(multiple striatal supernatant samples were serially diluted in duplicate in 96-well plates and the ELISA was carried out using a )] TJ ET BT 26.250 88.301 Td /F1 9.8 Tf [(combination of monoclonal and polyclonal antibodies to BDNF. Striatal BDNF values were determined by comparison to a )] TJ ET BT 26.250 76.396 Td /F1 9.8 Tf [(BDNF Standard curve \(0-500 pg/ml\). Final BDNF concentrations in striatal supernatants were calculated as pg/g total striatal )] TJ ET BT 26.250 64.491 Td /F1 9.8 Tf [(protein.)] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(2)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 184 0 obj << /Type /Font /Subtype /Type1 /Name /F5 /BaseFont /Helvetica-Oblique /Encoding /WinAnsiEncoding >> endobj 185 0 obj << /Type /Annot /Subtype /Link /A 186 0 R /Border [0 0 0] /H /I /Rect [ 129.7463 766.5743 146.0093 776.4950 ] >> endobj 186 0 obj << /Type /Action >> endobj 187 0 obj << /Type /Annot /Subtype /Link /A 188 0 R /Border [0 0 0] /H /I /Rect [ 146.0093 766.5743 162.2723 776.4950 ] >> endobj 188 0 obj << /Type /Action >> endobj 189 0 obj << /Type /Annot /Subtype /Link /A 190 0 R /Border [0 0 0] /H /I /Rect [ 162.2723 766.5743 178.5353 776.4950 ] >> endobj 190 0 obj << /Type /Action >> endobj 191 0 obj << /Type /Annot /Subtype /Link /A 192 0 R /Border [0 0 0] 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R6/2 mice and WT controls \(n=7 and 6, )] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(respectively\). In some additional experiments mice expressing enhanced green fluorescent protein \(EGFP\) in A)] TJ ET BT 505.813 734.102 Td /F1 8.7 Tf [(2A)] TJ ET BT 516.413 736.167 Td /F1 9.8 Tf [( or D2 )] TJ ET BT 26.250 724.262 Td /F1 9.8 Tf [(receptor-containing MSSNs were used to examine adenosine receptor modulation specifically in this subpopulation of neurons )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(that originate the indirect striatal output pathway.)] TJ ET BT 26.250 692.952 Td /F4 9.8 Tf [(Ampakines:)] TJ ET BT 26.250 673.548 Td /F1 9.8 Tf [(Experiments were conducted in two age groups of R6/2 and WT controls: a middle-agegroup \(5-7 weeks; n=12 R6/2 and 14 )] TJ ET BT 26.250 661.643 Td /F1 9.8 Tf [(WT\) corresponding to theonset of motor symptoms, and an older group \(11-12 weeks; n= 7 R6/2 and 7 WT\) displaying the full )] TJ ET BT 26.250 649.738 Td /F1 9.8 Tf [(behavioral phenotype.)] TJ ET BT 26.250 630.333 Td /F4 9.8 Tf [(Slice Electrophysiology:)] TJ ET BT 139.496 630.333 Td /F1 9.8 Tf [( After sacrifice, the brains were dissected and immediatelyplaced in oxygenated ice-cold low-Ca )] TJ ET BT 555.110 634.222 Td /F1 8.7 Tf [(2+)] TJ ET BT 26.250 618.429 Td /F1 9.8 Tf [(artificial cerebrospinalfluid \(ACSF\) containing \(in mM\) NaCl, 130; NaH)] TJ ET BT 327.486 616.364 Td /F1 8.7 Tf [(2)] TJ ET BT 332.305 618.429 Td /F1 9.8 Tf [( PO)] TJ ET BT 349.104 616.364 Td /F1 8.7 Tf [(4)] TJ ET BT 353.923 618.429 Td /F1 9.8 Tf [( , 1.25; NaHCO)] TJ ET BT 420.574 616.364 Td /F1 8.7 Tf [(3)] TJ ET BT 425.392 618.429 Td /F1 9.8 Tf [( ,26; MgCl)] TJ ET BT 469.823 616.364 Td /F1 8.7 Tf [(2)] TJ ET BT 474.642 618.429 Td /F1 9.8 Tf [( , 5; CaCl)] TJ ET BT 515.280 616.364 Td /F1 8.7 Tf [(2)] TJ ET BT 520.098 618.429 Td /F1 9.8 Tf [( , 1; and )] TJ ET BT 26.250 606.524 Td /F1 9.8 Tf [(glucose, 10. The hemispheres wereseparated and 350 m coronal slices were cut and transferredto an incubating chamber )] TJ ET BT 26.250 594.619 Td /F1 9.8 Tf [(containing ACSF \(with 2 mM CaCl)] TJ ET BT 174.157 592.555 Td /F1 8.7 Tf [(2)] TJ ET BT 178.976 594.619 Td /F1 9.8 Tf [( and2 mM MgCl)] TJ ET BT 247.782 592.555 Td /F1 8.7 Tf [(2)] TJ ET BT 252.601 594.619 Td /F1 9.8 Tf [( \) oxygenated with 95% O )] TJ ET BT 366.949 592.555 Td /F1 8.7 Tf [(2)] TJ ET BT 371.767 594.619 Td /F1 9.8 Tf [( -5% CO )] TJ ET BT 411.859 592.555 Td /F1 8.7 Tf [(2)] TJ ET BT 416.678 594.619 Td /F1 9.8 Tf [( \(pH 7.2-7.4,290-310 mOsm, )] TJ ET BT 26.250 582.714 Td /F1 9.8 Tf [(252C\). After 1 h slices wereplaced on the stage of an upright Olympus microscope \(BX51\),submerged in continuously flowing )] TJ ET BT 26.250 570.810 Td /F1 9.8 Tf [(ACSF \(~3 ml/min\). Nomarski optics and infrared videomicroscopy \(IR-DIC\) were used to identify MSSNs in slices )] TJ ET 0.267 0.267 0.267 rg BT 515.759 570.810 Td /F1 9.8 Tf [([37])] TJ ET 0.271 0.267 0.267 rg BT 532.022 570.810 Td /F1 9.8 Tf [( . A)] TJ ET BT 546.656 568.745 Td /F1 8.7 Tf [(2A)] TJ ET BT 26.250 558.905 Td /F1 9.8 Tf [(receptor expressing EGFP-positive cells were excited with UV light and visualized using fluorescence microscopy )] TJ ET 0.267 0.267 0.267 rg BT 517.163 558.905 Td /F1 9.8 Tf [([38])] TJ ET 0.271 0.267 0.267 rg BT 533.426 558.905 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 539.500 Td /F1 9.8 Tf [(Whole-cellpatch clamp recordings in voltage clamp mode were obtained fromMSSNs using an Axopatch 200B or Multiclamp )] TJ ET BT 26.250 527.595 Td /F1 9.8 Tf [(700B amplifier operated under pClamp \(versions 8 and 10, respectively\). MSSNs were identified by somatic size and typical )] TJ ET BT 26.250 515.691 Td /F1 9.8 Tf [(basic membrane properties \(input resistance, membrane capacitance,and time constant\). The patch pipette \(3-5 MO )] TJ ET BT 26.250 503.786 Td /F1 9.8 Tf [(impedance\) contained the following solution\(in mM\): 130 Cs-methanesulfonate, 10 CsCl, 4 NaCl, 1 MgCl)] TJ ET BT 477.080 501.722 Td /F1 8.7 Tf [(2)] TJ ET BT 481.899 503.786 Td /F1 9.8 Tf [( , 5 MgATP, 5 EGTA, )] TJ ET BT 26.250 491.881 Td /F1 9.8 Tf [(10 HEPES, 0.5 GTP, 10 phosphocreatine, and 0.1 leupeptin, pH 7.25-7.3 \(osmolality, 280-290 mOsm\). Series resistance was )] TJ ET BT 26.250 479.976 Td /F1 9.8 Tf [(less than 25 MO and was compensated optimally by the automatic compensation function included in the pClamp software.)] TJ ET BT 26.250 460.572 Td /F1 9.8 Tf [(Spontaneous EPSCs were examined in isolation by holding the membrane at -70 mV and, in most cases, using bicuculline )] TJ ET BT 26.250 448.667 Td /F1 9.8 Tf [(\(BIC, 10 M\) to block spontaneous activity mediated by activation of GABA)] TJ ET BT 349.228 446.603 Td /F1 8.7 Tf [(A)] TJ ET BT 355.009 448.667 Td /F1 9.8 Tf [( receptors.The membrane currentwas filtered at 1 )] TJ ET BT 26.250 436.762 Td /F1 9.8 Tf [(kHz and sampled at 20 kHz. In some experiments, tetrodotoxin \(TTX, 1 M\) was included in the extracellular solutionto isolate )] TJ ET BT 26.250 424.857 Td /F1 9.8 Tf [(the events that are not dependent on presynaptic actionpotentials [miniature EPSCs \(mEPSCs\)]. Spontaneous synaptic events )] TJ ET BT 26.250 412.953 Td /F1 9.8 Tf [(were analyzed off-line using the Mini Analysis 6.0 Program \(Jaejin Software, Leonia, NJ\). This software was usedto calculate )] TJ ET BT 26.250 401.048 Td /F1 9.8 Tf [(EPSC frequency, amplitude for each event, and toconstruct amplitude-frequency and inter-event interval histograms. The )] TJ ET BT 26.250 389.143 Td /F1 9.8 Tf [(thresholdamplitude for the detection of an event was adjusted above root-mean-square noise level \(~2-3 pA\) and )] TJ ET BT 26.250 377.238 Td /F1 9.8 Tf [(frequencieswere expressed as number of events per second \(inHz\). Analysis of EPSC kinetics was done using the Mini )] TJ ET BT 26.250 365.334 Td /F1 9.8 Tf [(Analysis Program. Events with peak amplitudes between 5 and 50 pA were grouped, alignedby half-rise time, and normalized )] TJ ET BT 26.250 353.429 Td /F1 9.8 Tf [(by peak amplitude. In each cell, all events between5 and 50 pA were averaged to obtain rise times, decay times,and half-)] TJ ET BT 26.250 341.524 Td /F1 9.8 Tf [(amplitude durations. Second-order exponentialcurves were fit with a maximum of 5000 iterations for computation of decay time.)] TJ ET BT 26.250 322.119 Td /F4 9.8 Tf [(Drugs:)] TJ ET BT 26.250 302.715 Td /F1 9.8 Tf [(A )] TJ ET BT 35.464 300.650 Td /F1 8.7 Tf [(2A)] TJ ET BT 46.063 302.715 Td /F1 9.8 Tf [( receptor agonists \(CGS 21680\) and antagonists \(KW 6002\) were obtained from Sigma and the Cure HD Initiative, Inc., )] TJ ET BT 26.250 290.810 Td /F1 9.8 Tf [(respectively. They were applied in the bath to examine their effects on spontaneous synaptic activity. Cx614 \(gift from Cortex )] TJ ET BT 26.250 278.905 Td /F1 9.8 Tf [(Pharmaceutical, Irvine, CA\) was dissolved in DMSO \(0.1%\) at a concentration of 200 mM and stored at -20C. Before the )] TJ ET BT 26.250 267.000 Td /F1 9.8 Tf [(experiments, the drug was diluted with ACSF solution to the desired concentration.)] TJ ET BT 26.250 247.596 Td /F4 9.8 Tf [(Statistics:)] TJ ET BT 26.250 228.191 Td /F1 9.8 Tf [(Values in the figures and text are presented as meansSEs. Differences among group means were assessed with appropriate )] TJ ET BT 26.250 216.286 Td /F1 9.8 Tf [(one or two-wayANOVAs followed by Fishers post hoc tests \(for running wheel analysis\) or Students )] TJ ET BT 461.909 216.286 Td /F5 9.8 Tf [(t)] TJ ET BT 464.620 216.286 Td /F1 9.8 Tf [( test when only two )] TJ ET BT 26.250 204.381 Td /F1 9.8 Tf [(groups were compared. Differenceswere considered statistically significant if )] TJ ET BT 358.403 204.381 Td /F5 9.8 Tf [(p)] TJ ET BT 363.824 204.381 Td /F1 9.8 Tf [( < 0.05.)] TJ ET BT 26.250 167.779 Td /F4 12.0 Tf [(Results)] TJ ET BT 26.250 147.825 Td /F4 9.8 Tf [(Exercise:)] TJ ET BT 26.250 128.420 Td /F1 9.8 Tf [(Both WT and R6/2 transgenic mice ran in the wheels and there were no significant differences in total average activity between )] TJ ET BT 26.250 116.515 Td /F1 9.8 Tf [(WT or transgenic males and females. Previously, we demonstrated profound deficits in running wheel behavior in R6/2 mice by )] TJ ET BT 26.250 104.610 Td /F1 9.8 Tf [(4.5 weeks of age )] TJ ET 0.267 0.267 0.267 rg BT 102.671 104.610 Td /F1 9.8 Tf [([34])] TJ ET 0.271 0.267 0.267 rg BT 118.934 104.610 Td /F1 9.8 Tf [( . Here, mice were exposed to running wheels for a longer period of time, and from an earlier age. As )] TJ ET BT 26.250 92.706 Td /F1 9.8 Tf [(expected, most running occurred during the dark cycle. As previously shown )] TJ ET 0.267 0.267 0.267 rg BT 357.887 92.706 Td /F1 9.8 Tf [([34])] TJ ET 0.271 0.267 0.267 rg BT 374.149 92.706 Td /F1 9.8 Tf [( , during the light cycle there were no )] TJ ET BT 26.250 80.801 Td /F1 9.8 Tf [(significant differences between WT and R6/2 at this age. R6/2 mice ran significantly less than WT animals during the dark cycle )] TJ ET BT 26.250 68.896 Td /F1 9.8 Tf [(\(Figure 1; effect of genotype F\(1,16\)=28.01, p<0.0001\). The difference was significant from the 6)] TJ ET BT 442.468 72.784 Td /F1 8.7 Tf [(th)] TJ ET BT 449.696 68.896 Td /F1 9.8 Tf [( day in the running wheel )] TJ ET BT 26.250 56.991 Td /F1 9.8 Tf [(cage \(27 days of age\) and lasted throughout the duration of the experiment.)] TJ ET Q q 15.000 47.110 577.500 729.890 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F4 9.8 Tf [(Adenosine A)] TJ ET BT 85.842 765.412 Td /F4 8.7 Tf [(2A)] TJ ET BT 96.918 767.476 Td /F4 9.8 Tf [( Receptors:)] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(Experiments were conducted in pre- \(21-41 days, n=7\) or symptomatic \(>60 days, n=5\) R6/2 mice and WT controls \(n=7 and 6, )] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(respectively\). In some additional experiments mice expressing enhanced green fluorescent protein \(EGFP\) in A)] TJ ET BT 505.813 734.102 Td /F1 8.7 Tf [(2A)] TJ ET BT 516.413 736.167 Td /F1 9.8 Tf [( or D2 )] TJ ET BT 26.250 724.262 Td /F1 9.8 Tf [(receptor-containing MSSNs were used to examine adenosine receptor modulation specifically in this subpopulation of neurons )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(that originate the indirect striatal output pathway.)] TJ ET BT 26.250 692.952 Td /F4 9.8 Tf [(Ampakines:)] TJ ET BT 26.250 673.548 Td /F1 9.8 Tf [(Experiments were conducted in two age groups of R6/2 and WT controls: a middle-agegroup \(5-7 weeks; n=12 R6/2 and 14 )] TJ ET BT 26.250 661.643 Td /F1 9.8 Tf [(WT\) corresponding to theonset of motor symptoms, and an older group \(11-12 weeks; n= 7 R6/2 and 7 WT\) displaying the full )] TJ ET BT 26.250 649.738 Td /F1 9.8 Tf [(behavioral phenotype.)] TJ ET BT 26.250 630.333 Td /F4 9.8 Tf [(Slice Electrophysiology:)] TJ ET BT 139.496 630.333 Td /F1 9.8 Tf [( After sacrifice, the brains were dissected and immediatelyplaced in oxygenated ice-cold low-Ca )] TJ ET BT 555.110 634.222 Td /F1 8.7 Tf [(2+)] TJ ET BT 26.250 618.429 Td /F1 9.8 Tf [(artificial cerebrospinalfluid \(ACSF\) containing \(in mM\) NaCl, 130; NaH)] TJ ET BT 327.486 616.364 Td /F1 8.7 Tf [(2)] TJ ET BT 332.305 618.429 Td /F1 9.8 Tf [( PO)] TJ ET BT 349.104 616.364 Td /F1 8.7 Tf [(4)] TJ ET BT 353.923 618.429 Td /F1 9.8 Tf [( , 1.25; NaHCO)] TJ ET BT 420.574 616.364 Td /F1 8.7 Tf [(3)] TJ ET BT 425.392 618.429 Td /F1 9.8 Tf [( ,26; MgCl)] TJ ET BT 469.823 616.364 Td /F1 8.7 Tf [(2)] TJ ET BT 474.642 618.429 Td /F1 9.8 Tf [( , 5; CaCl)] TJ ET BT 515.280 616.364 Td /F1 8.7 Tf [(2)] TJ ET BT 520.098 618.429 Td /F1 9.8 Tf [( , 1; and )] TJ ET BT 26.250 606.524 Td /F1 9.8 Tf [(glucose, 10. The hemispheres wereseparated and 350 m coronal slices were cut and transferredto an incubating chamber )] TJ ET BT 26.250 594.619 Td /F1 9.8 Tf [(containing ACSF \(with 2 mM CaCl)] TJ ET BT 174.157 592.555 Td /F1 8.7 Tf [(2)] TJ ET BT 178.976 594.619 Td /F1 9.8 Tf [( and2 mM MgCl)] TJ ET BT 247.782 592.555 Td /F1 8.7 Tf [(2)] TJ ET BT 252.601 594.619 Td /F1 9.8 Tf [( \) oxygenated with 95% O )] TJ ET BT 366.949 592.555 Td /F1 8.7 Tf [(2)] TJ ET BT 371.767 594.619 Td /F1 9.8 Tf [( -5% CO )] TJ ET BT 411.859 592.555 Td /F1 8.7 Tf [(2)] TJ ET BT 416.678 594.619 Td /F1 9.8 Tf [( \(pH 7.2-7.4,290-310 mOsm, )] TJ ET BT 26.250 582.714 Td /F1 9.8 Tf [(252C\). After 1 h slices wereplaced on the stage of an upright Olympus microscope \(BX51\),submerged in continuously flowing )] TJ ET BT 26.250 570.810 Td /F1 9.8 Tf [(ACSF \(~3 ml/min\). Nomarski optics and infrared videomicroscopy \(IR-DIC\) were used to identify MSSNs in slices )] TJ ET 0.267 0.267 0.267 rg BT 515.759 570.810 Td /F1 9.8 Tf [([37])] TJ ET 0.271 0.267 0.267 rg BT 532.022 570.810 Td /F1 9.8 Tf [( . A)] TJ ET BT 546.656 568.745 Td /F1 8.7 Tf [(2A)] TJ ET BT 26.250 558.905 Td /F1 9.8 Tf [(receptor expressing EGFP-positive cells were excited with UV light and visualized using fluorescence microscopy )] TJ ET 0.267 0.267 0.267 rg BT 517.163 558.905 Td /F1 9.8 Tf [([38])] TJ ET 0.271 0.267 0.267 rg BT 533.426 558.905 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 539.500 Td /F1 9.8 Tf [(Whole-cellpatch clamp recordings in voltage clamp mode were obtained fromMSSNs using an Axopatch 200B or Multiclamp )] TJ ET BT 26.250 527.595 Td /F1 9.8 Tf [(700B amplifier operated under pClamp \(versions 8 and 10, respectively\). MSSNs were identified by somatic size and typical )] TJ ET BT 26.250 515.691 Td /F1 9.8 Tf [(basic membrane properties \(input resistance, membrane capacitance,and time constant\). The patch pipette \(3-5 MO )] TJ ET BT 26.250 503.786 Td /F1 9.8 Tf [(impedance\) contained the following solution\(in mM\): 130 Cs-methanesulfonate, 10 CsCl, 4 NaCl, 1 MgCl)] TJ ET BT 477.080 501.722 Td /F1 8.7 Tf [(2)] TJ ET BT 481.899 503.786 Td /F1 9.8 Tf [( , 5 MgATP, 5 EGTA, )] TJ ET BT 26.250 491.881 Td /F1 9.8 Tf [(10 HEPES, 0.5 GTP, 10 phosphocreatine, and 0.1 leupeptin, pH 7.25-7.3 \(osmolality, 280-290 mOsm\). Series resistance was )] TJ ET BT 26.250 479.976 Td /F1 9.8 Tf [(less than 25 MO and was compensated optimally by the automatic compensation function included in the pClamp software.)] TJ ET BT 26.250 460.572 Td /F1 9.8 Tf [(Spontaneous EPSCs were examined in isolation by holding the membrane at -70 mV and, in most cases, using bicuculline )] TJ ET BT 26.250 448.667 Td /F1 9.8 Tf [(\(BIC, 10 M\) to block spontaneous activity mediated by activation of GABA)] TJ ET BT 349.228 446.603 Td /F1 8.7 Tf [(A)] TJ ET BT 355.009 448.667 Td /F1 9.8 Tf [( receptors.The membrane currentwas filtered at 1 )] TJ ET BT 26.250 436.762 Td /F1 9.8 Tf [(kHz and sampled at 20 kHz. In some experiments, tetrodotoxin \(TTX, 1 M\) was included in the extracellular solutionto isolate )] TJ ET BT 26.250 424.857 Td /F1 9.8 Tf [(the events that are not dependent on presynaptic actionpotentials [miniature EPSCs \(mEPSCs\)]. Spontaneous synaptic events )] TJ ET BT 26.250 412.953 Td /F1 9.8 Tf [(were analyzed off-line using the Mini Analysis 6.0 Program \(Jaejin Software, Leonia, NJ\). This software was usedto calculate )] TJ ET BT 26.250 401.048 Td /F1 9.8 Tf [(EPSC frequency, amplitude for each event, and toconstruct amplitude-frequency and inter-event interval histograms. The )] TJ ET BT 26.250 389.143 Td /F1 9.8 Tf [(thresholdamplitude for the detection of an event was adjusted above root-mean-square noise level \(~2-3 pA\) and )] TJ ET BT 26.250 377.238 Td /F1 9.8 Tf [(frequencieswere expressed as number of events per second \(inHz\). Analysis of EPSC kinetics was done using the Mini )] TJ ET BT 26.250 365.334 Td /F1 9.8 Tf [(Analysis Program. Events with peak amplitudes between 5 and 50 pA were grouped, alignedby half-rise time, and normalized )] TJ ET BT 26.250 353.429 Td /F1 9.8 Tf [(by peak amplitude. In each cell, all events between5 and 50 pA were averaged to obtain rise times, decay times,and half-)] TJ ET BT 26.250 341.524 Td /F1 9.8 Tf [(amplitude durations. Second-order exponentialcurves were fit with a maximum of 5000 iterations for computation of decay time.)] TJ ET BT 26.250 322.119 Td /F4 9.8 Tf [(Drugs:)] TJ ET BT 26.250 302.715 Td /F1 9.8 Tf [(A )] TJ ET BT 35.464 300.650 Td /F1 8.7 Tf [(2A)] TJ ET BT 46.063 302.715 Td /F1 9.8 Tf [( receptor agonists \(CGS 21680\) and antagonists \(KW 6002\) were obtained from Sigma and the Cure HD Initiative, Inc., )] TJ ET BT 26.250 290.810 Td /F1 9.8 Tf [(respectively. They were applied in the bath to examine their effects on spontaneous synaptic activity. Cx614 \(gift from Cortex )] TJ ET BT 26.250 278.905 Td /F1 9.8 Tf [(Pharmaceutical, Irvine, CA\) was dissolved in DMSO \(0.1%\) at a concentration of 200 mM and stored at -20C. Before the )] TJ ET BT 26.250 267.000 Td /F1 9.8 Tf [(experiments, the drug was diluted with ACSF solution to the desired concentration.)] TJ ET BT 26.250 247.596 Td /F4 9.8 Tf [(Statistics:)] TJ ET BT 26.250 228.191 Td /F1 9.8 Tf [(Values in the figures and text are presented as meansSEs. Differences among group means were assessed with appropriate )] TJ ET BT 26.250 216.286 Td /F1 9.8 Tf [(one or two-wayANOVAs followed by Fishers post hoc tests \(for running wheel analysis\) or Students )] TJ ET BT 461.909 216.286 Td /F5 9.8 Tf [(t)] TJ ET BT 464.620 216.286 Td /F1 9.8 Tf [( test when only two )] TJ ET BT 26.250 204.381 Td /F1 9.8 Tf [(groups were compared. Differenceswere considered statistically significant if )] TJ ET BT 358.403 204.381 Td /F5 9.8 Tf [(p)] TJ ET BT 363.824 204.381 Td /F1 9.8 Tf [( < 0.05.)] TJ ET BT 26.250 167.779 Td /F4 12.0 Tf [(Results)] TJ ET BT 26.250 147.825 Td /F4 9.8 Tf [(Exercise:)] TJ ET BT 26.250 128.420 Td /F1 9.8 Tf [(Both WT and R6/2 transgenic mice ran in the wheels and there were no significant differences in total average activity between )] TJ ET BT 26.250 116.515 Td /F1 9.8 Tf [(WT or transgenic males and females. Previously, we demonstrated profound deficits in running wheel behavior in R6/2 mice by )] TJ ET BT 26.250 104.610 Td /F1 9.8 Tf [(4.5 weeks of age )] TJ ET 0.267 0.267 0.267 rg BT 102.671 104.610 Td /F1 9.8 Tf [([34])] TJ ET 0.271 0.267 0.267 rg BT 118.934 104.610 Td /F1 9.8 Tf [( . Here, mice were exposed to running wheels for a longer period of time, and from an earlier age. As )] TJ ET BT 26.250 92.706 Td /F1 9.8 Tf [(expected, most running occurred during the dark cycle. As previously shown )] TJ ET 0.267 0.267 0.267 rg BT 357.887 92.706 Td /F1 9.8 Tf [([34])] TJ ET 0.271 0.267 0.267 rg BT 374.149 92.706 Td /F1 9.8 Tf [( , during the light cycle there were no )] TJ ET BT 26.250 80.801 Td /F1 9.8 Tf [(significant differences between WT and R6/2 at this age. R6/2 mice ran significantly less than WT animals during the dark cycle )] TJ ET BT 26.250 68.896 Td /F1 9.8 Tf [(\(Figure 1; effect of genotype F\(1,16\)=28.01, p<0.0001\). The difference was significant from the 6)] TJ ET BT 442.468 72.784 Td /F1 8.7 Tf [(th)] TJ ET BT 449.696 68.896 Td /F1 9.8 Tf [( day in the running wheel )] TJ ET BT 26.250 56.991 Td /F1 9.8 Tf [(cage \(27 days of age\) and lasted throughout the duration of the experiment.)] TJ ET Q q 15.000 47.110 577.500 729.890 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F4 9.8 Tf [(Adenosine A)] TJ ET BT 85.842 765.412 Td /F4 8.7 Tf [(2A)] TJ ET BT 96.918 767.476 Td /F4 9.8 Tf [( Receptors:)] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(Experiments were conducted in pre- \(21-41 days, n=7\) or symptomatic \(>60 days, n=5\) R6/2 mice and WT controls \(n=7 and 6, )] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(respectively\). In some additional experiments mice expressing enhanced green fluorescent protein \(EGFP\) in A)] TJ ET BT 505.813 734.102 Td /F1 8.7 Tf [(2A)] TJ ET BT 516.413 736.167 Td /F1 9.8 Tf [( or D2 )] TJ ET BT 26.250 724.262 Td /F1 9.8 Tf [(receptor-containing MSSNs were used to examine adenosine receptor modulation specifically in this subpopulation of neurons )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(that originate the indirect striatal output pathway.)] TJ ET BT 26.250 692.952 Td /F4 9.8 Tf [(Ampakines:)] TJ ET BT 26.250 673.548 Td /F1 9.8 Tf [(Experiments were conducted in two age groups of R6/2 and WT controls: a middle-agegroup \(5-7 weeks; n=12 R6/2 and 14 )] TJ ET BT 26.250 661.643 Td /F1 9.8 Tf [(WT\) corresponding to theonset of motor symptoms, and an older group \(11-12 weeks; n= 7 R6/2 and 7 WT\) displaying the full )] TJ ET BT 26.250 649.738 Td /F1 9.8 Tf [(behavioral phenotype.)] TJ ET BT 26.250 630.333 Td /F4 9.8 Tf [(Slice Electrophysiology:)] TJ ET BT 139.496 630.333 Td /F1 9.8 Tf [( After sacrifice, the brains were dissected and immediatelyplaced in oxygenated ice-cold low-Ca )] TJ ET BT 555.110 634.222 Td /F1 8.7 Tf [(2+)] TJ ET BT 26.250 618.429 Td /F1 9.8 Tf [(artificial cerebrospinalfluid \(ACSF\) containing \(in mM\) NaCl, 130; NaH)] TJ ET BT 327.486 616.364 Td /F1 8.7 Tf [(2)] TJ ET BT 332.305 618.429 Td /F1 9.8 Tf [( PO)] TJ ET BT 349.104 616.364 Td /F1 8.7 Tf [(4)] TJ ET BT 353.923 618.429 Td /F1 9.8 Tf [( , 1.25; NaHCO)] TJ ET BT 420.574 616.364 Td /F1 8.7 Tf [(3)] TJ ET BT 425.392 618.429 Td /F1 9.8 Tf [( ,26; MgCl)] TJ ET BT 469.823 616.364 Td /F1 8.7 Tf [(2)] TJ ET BT 474.642 618.429 Td /F1 9.8 Tf [( , 5; CaCl)] TJ ET BT 515.280 616.364 Td /F1 8.7 Tf [(2)] TJ ET BT 520.098 618.429 Td /F1 9.8 Tf [( , 1; and )] TJ ET BT 26.250 606.524 Td /F1 9.8 Tf [(glucose, 10. The hemispheres wereseparated and 350 m coronal slices were cut and transferredto an incubating chamber )] TJ ET BT 26.250 594.619 Td /F1 9.8 Tf [(containing ACSF \(with 2 mM CaCl)] TJ ET BT 174.157 592.555 Td /F1 8.7 Tf [(2)] TJ ET BT 178.976 594.619 Td /F1 9.8 Tf [( and2 mM MgCl)] TJ ET BT 247.782 592.555 Td /F1 8.7 Tf [(2)] TJ ET BT 252.601 594.619 Td /F1 9.8 Tf [( \) oxygenated with 95% O )] TJ ET BT 366.949 592.555 Td /F1 8.7 Tf [(2)] TJ ET BT 371.767 594.619 Td /F1 9.8 Tf [( -5% CO )] TJ ET BT 411.859 592.555 Td /F1 8.7 Tf [(2)] TJ ET BT 416.678 594.619 Td /F1 9.8 Tf [( \(pH 7.2-7.4,290-310 mOsm, )] TJ ET BT 26.250 582.714 Td /F1 9.8 Tf [(252C\). After 1 h slices wereplaced on the stage of an upright Olympus microscope \(BX51\),submerged in continuously flowing )] TJ ET BT 26.250 570.810 Td /F1 9.8 Tf [(ACSF \(~3 ml/min\). Nomarski optics and infrared videomicroscopy \(IR-DIC\) were used to identify MSSNs in slices )] TJ ET 0.267 0.267 0.267 rg BT 515.759 570.810 Td /F1 9.8 Tf [([37])] TJ ET 0.271 0.267 0.267 rg BT 532.022 570.810 Td /F1 9.8 Tf [( . A)] TJ ET BT 546.656 568.745 Td /F1 8.7 Tf [(2A)] TJ ET BT 26.250 558.905 Td /F1 9.8 Tf [(receptor expressing EGFP-positive cells were excited with UV light and visualized using fluorescence microscopy )] TJ ET 0.267 0.267 0.267 rg BT 517.163 558.905 Td /F1 9.8 Tf [([38])] TJ ET 0.271 0.267 0.267 rg BT 533.426 558.905 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 539.500 Td /F1 9.8 Tf [(Whole-cellpatch clamp recordings in voltage clamp mode were obtained fromMSSNs using an Axopatch 200B or Multiclamp )] TJ ET BT 26.250 527.595 Td /F1 9.8 Tf [(700B amplifier operated under pClamp \(versions 8 and 10, respectively\). MSSNs were identified by somatic size and typical )] TJ ET BT 26.250 515.691 Td /F1 9.8 Tf [(basic membrane properties \(input resistance, membrane capacitance,and time constant\). The patch pipette \(3-5 MO )] TJ ET BT 26.250 503.786 Td /F1 9.8 Tf [(impedance\) contained the following solution\(in mM\): 130 Cs-methanesulfonate, 10 CsCl, 4 NaCl, 1 MgCl)] TJ ET BT 477.080 501.722 Td /F1 8.7 Tf [(2)] TJ ET BT 481.899 503.786 Td /F1 9.8 Tf [( , 5 MgATP, 5 EGTA, )] TJ ET BT 26.250 491.881 Td /F1 9.8 Tf [(10 HEPES, 0.5 GTP, 10 phosphocreatine, and 0.1 leupeptin, pH 7.25-7.3 \(osmolality, 280-290 mOsm\). Series resistance was )] TJ ET BT 26.250 479.976 Td /F1 9.8 Tf [(less than 25 MO and was compensated optimally by the automatic compensation function included in the pClamp software.)] TJ ET BT 26.250 460.572 Td /F1 9.8 Tf [(Spontaneous EPSCs were examined in isolation by holding the membrane at -70 mV and, in most cases, using bicuculline )] TJ ET BT 26.250 448.667 Td /F1 9.8 Tf [(\(BIC, 10 M\) to block spontaneous activity mediated by activation of GABA)] TJ ET BT 349.228 446.603 Td /F1 8.7 Tf [(A)] TJ ET BT 355.009 448.667 Td /F1 9.8 Tf [( receptors.The membrane currentwas filtered at 1 )] TJ ET BT 26.250 436.762 Td /F1 9.8 Tf [(kHz and sampled at 20 kHz. In some experiments, tetrodotoxin \(TTX, 1 M\) was included in the extracellular solutionto isolate )] TJ ET BT 26.250 424.857 Td /F1 9.8 Tf [(the events that are not dependent on presynaptic actionpotentials [miniature EPSCs \(mEPSCs\)]. Spontaneous synaptic events )] TJ ET BT 26.250 412.953 Td /F1 9.8 Tf [(were analyzed off-line using the Mini Analysis 6.0 Program \(Jaejin Software, Leonia, NJ\). This software was usedto calculate )] TJ ET BT 26.250 401.048 Td /F1 9.8 Tf [(EPSC frequency, amplitude for each event, and toconstruct amplitude-frequency and inter-event interval histograms. The )] TJ ET BT 26.250 389.143 Td /F1 9.8 Tf [(thresholdamplitude for the detection of an event was adjusted above root-mean-square noise level \(~2-3 pA\) and )] TJ ET BT 26.250 377.238 Td /F1 9.8 Tf [(frequencieswere expressed as number of events per second \(inHz\). Analysis of EPSC kinetics was done using the Mini )] TJ ET BT 26.250 365.334 Td /F1 9.8 Tf [(Analysis Program. Events with peak amplitudes between 5 and 50 pA were grouped, alignedby half-rise time, and normalized )] TJ ET BT 26.250 353.429 Td /F1 9.8 Tf [(by peak amplitude. In each cell, all events between5 and 50 pA were averaged to obtain rise times, decay times,and half-)] TJ ET BT 26.250 341.524 Td /F1 9.8 Tf [(amplitude durations. Second-order exponentialcurves were fit with a maximum of 5000 iterations for computation of decay time.)] TJ ET BT 26.250 322.119 Td /F4 9.8 Tf [(Drugs:)] TJ ET BT 26.250 302.715 Td /F1 9.8 Tf [(A )] TJ ET BT 35.464 300.650 Td /F1 8.7 Tf [(2A)] TJ ET BT 46.063 302.715 Td /F1 9.8 Tf [( receptor agonists \(CGS 21680\) and antagonists \(KW 6002\) were obtained from Sigma and the Cure HD Initiative, Inc., )] TJ ET BT 26.250 290.810 Td /F1 9.8 Tf [(respectively. They were applied in the bath to examine their effects on spontaneous synaptic activity. Cx614 \(gift from Cortex )] TJ ET BT 26.250 278.905 Td /F1 9.8 Tf [(Pharmaceutical, Irvine, CA\) was dissolved in DMSO \(0.1%\) at a concentration of 200 mM and stored at -20C. Before the )] TJ ET BT 26.250 267.000 Td /F1 9.8 Tf [(experiments, the drug was diluted with ACSF solution to the desired concentration.)] TJ ET BT 26.250 247.596 Td /F4 9.8 Tf [(Statistics:)] TJ ET BT 26.250 228.191 Td /F1 9.8 Tf [(Values in the figures and text are presented as meansSEs. Differences among group means were assessed with appropriate )] TJ ET BT 26.250 216.286 Td /F1 9.8 Tf [(one or two-wayANOVAs followed by Fishers post hoc tests \(for running wheel analysis\) or Students )] TJ ET BT 461.909 216.286 Td /F5 9.8 Tf [(t)] TJ ET BT 464.620 216.286 Td /F1 9.8 Tf [( test when only two )] TJ ET BT 26.250 204.381 Td /F1 9.8 Tf [(groups were compared. Differenceswere considered statistically significant if )] TJ ET BT 358.403 204.381 Td /F5 9.8 Tf [(p)] TJ ET BT 363.824 204.381 Td /F1 9.8 Tf [( < 0.05.)] TJ ET BT 26.250 167.779 Td /F4 12.0 Tf [(Results)] TJ ET BT 26.250 147.825 Td /F4 9.8 Tf [(Exercise:)] TJ ET BT 26.250 128.420 Td /F1 9.8 Tf [(Both WT and R6/2 transgenic mice ran in the wheels and there were no significant differences in total average activity between )] TJ ET BT 26.250 116.515 Td /F1 9.8 Tf [(WT or transgenic males and females. Previously, we demonstrated profound deficits in running wheel behavior in R6/2 mice by )] TJ ET BT 26.250 104.610 Td /F1 9.8 Tf [(4.5 weeks of age )] TJ ET 0.267 0.267 0.267 rg BT 102.671 104.610 Td /F1 9.8 Tf [([34])] TJ ET 0.271 0.267 0.267 rg BT 118.934 104.610 Td /F1 9.8 Tf [( . Here, mice were exposed to running wheels for a longer period of time, and from an earlier age. As )] TJ ET BT 26.250 92.706 Td /F1 9.8 Tf [(expected, most running occurred during the dark cycle. As previously shown )] TJ ET 0.267 0.267 0.267 rg BT 357.887 92.706 Td /F1 9.8 Tf [([34])] TJ ET 0.271 0.267 0.267 rg BT 374.149 92.706 Td /F1 9.8 Tf [( , during the light cycle there were no )] TJ ET BT 26.250 80.801 Td /F1 9.8 Tf [(significant differences between WT and R6/2 at this age. R6/2 mice ran significantly less than WT animals during the dark cycle )] TJ ET BT 26.250 68.896 Td /F1 9.8 Tf [(\(Figure 1; effect of genotype F\(1,16\)=28.01, p<0.0001\). The difference was significant from the 6)] TJ ET BT 442.468 72.784 Td /F1 8.7 Tf [(th)] TJ ET BT 449.696 68.896 Td /F1 9.8 Tf [( day in the running wheel )] TJ ET BT 26.250 56.991 Td /F1 9.8 Tf [(cage \(27 days of age\) and lasted throughout the duration of the experiment.)] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(3)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 319 0 obj << /Type /Annot /Subtype /Link /A 320 0 R /Border [0 0 0] /H /I /Rect [ 515.7585 569.9078 532.0215 579.8284 ] >> endobj 320 0 obj << /Type /Action >> endobj 321 0 obj << /Type /Annot /Subtype /Link /A 322 0 R /Border [0 0 0] /H /I /Rect [ 517.1625 558.0031 533.4255 567.9237 ] >> endobj 322 0 obj << /Type /Action >> endobj 323 0 obj << /Type /Annot /Subtype /Link /A 324 0 R /Border [0 0 0] /H /I /Rect [ 102.6705 103.7086 118.9335 113.6292 ] >> endobj 324 0 obj << /Type /Action >> endobj 325 0 obj << /Type /Annot /Subtype /Link /A 326 0 R /Border [0 0 0] /H /I /Rect [ 357.8865 91.8038 374.1495 101.7245 ] >> endobj 326 0 obj << /Type /Action >> endobj 327 0 obj << /Type /Annot /Subtype /Link /A 328 0 R /Border [0 0 0] /H /I /Rect [ 515.7585 569.9078 532.0215 579.8284 ] >> endobj 328 0 obj << /Type /Action >> endobj 329 0 obj << /Type /Annot /Subtype /Link /A 330 0 R /Border [0 0 0] /H /I /Rect [ 517.1625 558.0031 533.4255 567.9237 ] >> endobj 330 0 obj << /Type /Action >> endobj 331 0 obj << /Type /Annot /Subtype /Link /A 332 0 R /Border [0 0 0] /H /I /Rect [ 102.6705 103.7086 118.9335 113.6292 ] >> endobj 332 0 obj << /Type /Action >> endobj 333 0 obj << /Type /Annot /Subtype /Link /A 334 0 R /Border [0 0 0] /H /I /Rect [ 357.8865 91.8038 374.1495 101.7245 ] >> endobj 334 0 obj << /Type /Action >> endobj 335 0 obj << /Type /Annot /Subtype /Link /A 336 0 R /Border [0 0 0] /H /I /Rect [ 515.7585 569.9078 532.0215 579.8284 ] >> endobj 336 0 obj << /Type /Action >> endobj 337 0 obj << /Type /Annot /Subtype /Link /A 338 0 R /Border [0 0 0] /H /I /Rect [ 517.1625 558.0031 533.4255 567.9237 ] >> endobj 338 0 obj << /Type /Action >> endobj 339 0 obj << /Type /Annot /Subtype /Link /A 340 0 R /Border [0 0 0] /H /I /Rect [ 102.6705 103.7086 118.9335 113.6292 ] >> endobj 340 0 obj << /Type /Action >> endobj 341 0 obj << /Type /Annot /Subtype /Link /A 342 0 R /Border [0 0 0] /H /I /Rect [ 357.8865 91.8038 374.1495 101.7245 ] >> endobj 342 0 obj << /Type /Action >> endobj 343 0 obj << /Type /Page /Parent 3 0 R /Annots [ 345 0 R 348 0 R 350 0 R 352 0 R 354 0 R 356 0 R 358 0 R 360 0 R 362 0 R 364 0 R 366 0 R 368 0 R ] /Contents 344 0 R >> endobj 344 0 obj << /Length 26094 >> stream 0.271 0.267 0.267 rg q 15.000 31.688 577.500 745.312 re W n 0.965 0.965 0.965 rg 26.250 400.110 555.000 376.890 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 777.000 m 581.250 777.000 l 581.250 776.250 l 26.250 776.250 l f 26.250 400.110 m 581.250 400.110 l 581.250 400.860 l 26.250 400.860 l f q 153.000 0 0 225.000 35.250 542.250 cm /I3 Do Q q 35.250 411.360 537.000 124.890 re W n 0.271 0.267 0.267 rg BT 35.250 525.261 Td /F4 9.8 Tf [(Fig. 1:)] TJ ET BT 35.250 504.025 Td /F4 9.8 Tf [(A.)] TJ ET BT 45.000 504.025 Td /F1 9.8 Tf [( Examples of actograms from male and female WT \(left\) and R6/2 \(right\) mice during the light and dark cycles. R6/2 mice )] TJ ET BT 35.250 490.288 Td /F1 9.8 Tf [(displayed reduced activity compared to WTs. Each value represents the number of rotations per 3 min. The bars under the )] TJ ET BT 35.250 476.552 Td /F1 9.8 Tf [(actograms show the light and dark 12 h cycles. These actograms were obtained during the 3 days preceding the )] TJ ET BT 35.250 462.816 Td /F1 9.8 Tf [(electrophysiological recordings. The number of days in the running wheel cage is also indicated. )] TJ ET BT 451.975 462.816 Td /F4 9.8 Tf [(B)] TJ ET BT 459.014 462.816 Td /F1 9.8 Tf [(. Average activity during )] TJ ET BT 35.250 449.080 Td /F1 9.8 Tf [(the dark and light cycles. Throughout the duration of the experiment, R6/2 mice displayed lower levels of activity than WTs )] TJ ET BT 35.250 435.343 Td /F1 9.8 Tf [(in the dark. The differences were statistically significant \(p<0.01\) from the sixth day on \(indicated by the line and asterisks\). )] TJ ET BT 35.250 421.607 Td /F1 9.8 Tf [(There were no significant differences during the light cycle.)] TJ ET Q BT 26.250 383.086 Td /F1 9.8 Tf [(MSSNs from non-running transgenic mice had reduced membrane capacitance and increased input resistance compared to )] TJ ET BT 26.250 371.181 Td /F1 9.8 Tf [(WTs. These changes have been reported previously and probably indicate loss of cell membrane area )] TJ ET 0.267 0.267 0.267 rg BT 470.070 371.181 Td /F1 9.8 Tf [([8])] TJ ET BT 480.912 371.181 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 491.754 371.181 Td /F1 9.8 Tf [( as well as reduced )] TJ ET BT 26.250 359.277 Td /F1 9.8 Tf [(density of K )] TJ ET BT 79.904 363.165 Td /F1 8.7 Tf [(+)] TJ ET BT 84.966 359.277 Td /F1 9.8 Tf [( channels )] TJ ET 0.267 0.267 0.267 rg BT 129.406 359.277 Td /F1 9.8 Tf [([39])] TJ ET 0.271 0.267 0.267 rg BT 145.669 359.277 Td /F1 9.8 Tf [( . Running alleviated the significant difference in cell membrane capacitance between the groups )] TJ ET BT 26.250 347.372 Td /F1 9.8 Tf [(\(i.e., the difference between WT and R6/2 mice was no longer statistically significant\) \(Table 1\). In contrast, the increase in input )] TJ ET BT 26.250 335.467 Td /F1 9.8 Tf [(resistance in R6/2 mice was only slightly alleviated by exercise \(i.e., the magnitude of the increase in input resistance was )] TJ ET BT 26.250 323.562 Td /F1 9.8 Tf [(diminished but the difference between WT and R6/2 mice was still statistically significant\) \(Table 1\). The membrane time )] TJ ET BT 26.250 311.658 Td /F1 9.8 Tf [(constant \(t\) was not statistically different in the non-running or running groups \(Table 1\).)] TJ ET q 26.250 288.040 555.000 13.736 re W n 0.271 0.267 0.267 rg BT 26.250 290.788 Td /F1 9.8 Tf [(Table 1: Effects of Exercise on Basic Membrane Properties of MSSNs)] TJ ET Q 1.000 1.000 1.000 rg 26.250 203.236 555.000 77.305 re f 0.965 0.965 0.965 rg 27.000 267.511 188.337 12.280 re f 0.267 0.267 0.267 rg 26.625 279.415 188.712 0.750 re f 26.625 267.136 0.750 13.030 re f 0.965 0.965 0.965 rg 215.337 267.511 127.695 12.280 re f 0.267 0.267 0.267 rg 215.337 279.415 127.695 0.750 re f 0.271 0.267 0.267 rg BT 219.837 270.267 Td /F4 9.8 Tf [(Cm \(pF\))] TJ ET 0.965 0.965 0.965 rg 343.032 267.511 119.129 12.280 re f 0.267 0.267 0.267 rg 343.032 279.415 119.129 0.750 re f 0.271 0.267 0.267 rg BT 347.532 270.267 Td /F4 9.8 Tf [(Rm \(MO\))] TJ ET 0.965 0.965 0.965 rg 462.161 267.511 118.339 12.280 re f 0.267 0.267 0.267 rg 462.161 279.415 118.714 0.750 re f 580.125 267.136 0.750 13.030 re f 0.271 0.267 0.267 rg BT 466.661 270.267 Td /F4 9.8 Tf [(t \(ms\))] TJ ET 0.267 0.267 0.267 rg 26.625 267.136 189.087 0.750 re f 26.625 251.254 0.750 16.631 re f 0.271 0.267 0.267 rg BT 31.875 257.281 Td /F4 9.8 Tf [(WT Non-Running)] TJ ET 0.267 0.267 0.267 rg 214.962 267.136 128.445 0.750 re f 214.962 251.254 0.750 16.631 re f 0.271 0.267 0.267 rg BT 220.212 257.281 Td /F1 9.8 Tf [(83.44.1)] TJ ET 0.267 0.267 0.267 rg 342.657 267.136 119.879 0.750 re f 342.657 251.254 0.750 16.631 re f 0.271 0.267 0.267 rg BT 347.907 257.281 Td /F1 9.8 Tf [(727.2)] TJ ET 0.267 0.267 0.267 rg 461.786 267.136 119.089 0.750 re f 461.786 251.254 0.750 16.631 re f 580.125 251.254 0.750 16.631 re f 0.271 0.267 0.267 rg BT 467.036 257.281 Td /F1 9.8 Tf [(1.60.08)] TJ ET 0.267 0.267 0.267 rg 26.625 251.254 189.087 0.750 re f 26.625 235.373 0.750 16.631 re f 0.271 0.267 0.267 rg BT 31.875 241.399 Td /F4 9.8 Tf [(R6/2 Non-Running)] TJ ET 0.267 0.267 0.267 rg 214.962 251.254 128.445 0.750 re f 214.962 235.373 0.750 16.631 re f 0.271 0.267 0.267 rg BT 220.212 241.399 Td /F1 9.8 Tf [(70.33.6*)] TJ ET 0.267 0.267 0.267 rg 342.657 251.254 119.879 0.750 re f 342.657 235.373 0.750 16.631 re f 0.271 0.267 0.267 rg BT 347.907 241.399 Td /F1 9.8 Tf [(12616*)] TJ ET 0.267 0.267 0.267 rg 461.786 251.254 119.089 0.750 re f 461.786 235.373 0.750 16.631 re f 580.125 235.373 0.750 16.631 re f 0.271 0.267 0.267 rg BT 467.036 241.399 Td /F1 9.8 Tf [(1.40.06)] TJ ET 0.267 0.267 0.267 rg 26.625 235.373 189.087 0.750 re f 26.625 219.492 0.750 16.631 re f 0.271 0.267 0.267 rg BT 31.875 225.518 Td /F4 9.8 Tf [(WT Running)] TJ ET 0.267 0.267 0.267 rg 214.962 235.373 128.445 0.750 re f 214.962 219.492 0.750 16.631 re f 0.271 0.267 0.267 rg BT 220.212 225.518 Td /F1 9.8 Tf [(74.83.7)] TJ ET 0.267 0.267 0.267 rg 342.657 235.373 119.879 0.750 re f 342.657 219.492 0.750 16.631 re f 0.271 0.267 0.267 rg BT 347.907 225.518 Td /F1 9.8 Tf [(797.7)] TJ ET 0.267 0.267 0.267 rg 461.786 235.373 119.089 0.750 re f 461.786 219.492 0.750 16.631 re f 580.125 219.492 0.750 16.631 re f 0.271 0.267 0.267 rg BT 467.036 225.518 Td /F1 9.8 Tf [(1.40.07)] TJ ET 0.267 0.267 0.267 rg 26.625 219.492 189.087 0.750 re f 26.625 203.611 189.087 0.750 re f 26.625 203.611 0.750 16.631 re f 0.271 0.267 0.267 rg BT 31.875 209.637 Td /F4 9.8 Tf [(R6/2 Running)] TJ ET 0.267 0.267 0.267 rg 214.962 219.492 128.445 0.750 re f 214.962 203.611 128.445 0.750 re f 214.962 203.611 0.750 16.631 re f 0.271 0.267 0.267 rg BT 220.212 209.637 Td /F1 9.8 Tf [(84.13.6)] TJ ET 0.267 0.267 0.267 rg 342.657 219.492 119.879 0.750 re f 342.657 203.611 119.879 0.750 re f 342.657 203.611 0.750 16.631 re f 0.271 0.267 0.267 rg BT 347.907 209.637 Td /F1 9.8 Tf [(1097*)] TJ ET 0.267 0.267 0.267 rg 461.786 219.492 119.089 0.750 re f 461.786 203.611 119.089 0.750 re f 461.786 203.611 0.750 16.631 re f 580.125 203.611 0.750 16.631 re f 0.271 0.267 0.267 rg BT 467.036 209.637 Td /F1 9.8 Tf [(1.60.06)] TJ ET BT 26.250 148.712 Td /F1 9.8 Tf [(MSSNs from non-running transgenic mice had significantly reduced membrane capacitance \(Cm\) compared to WTs. Running )] TJ ET BT 26.250 136.807 Td /F1 9.8 Tf [(alleviated the significant difference in cell membrane capacitance between the groups. In contrast, the significant increase in )] TJ ET BT 26.250 124.902 Td /F1 9.8 Tf [(input resistance \(Rm\) in R6/2 mice was only partially alleviated by exercise. Time constant \(t\) was not significantly different in )] TJ ET BT 26.250 112.998 Td /F1 9.8 Tf [(non-running and running mice. Asterisks indicate the differences between WT and R6/2 mice were statistically significant.)] TJ ET BT 26.250 93.593 Td /F1 9.8 Tf [(Spontaneous EPSCs for all experiments were recorded at -70 mV holding potential. They were mediated by AMPA/kainate )] TJ ET BT 26.250 81.688 Td /F1 9.8 Tf [(glutamate receptors as they were almost completely abolished by CNQX, a non-NMDA receptor antagonist. Exercise produced )] TJ ET BT 26.250 69.783 Td /F1 9.8 Tf [(a non-significant increase in the frequency of spontaneous synaptic events in WT animals in ACSF \(Figure 2B, left graphs\). )] TJ ET BT 26.250 57.879 Td /F1 9.8 Tf [(After pharmacological isolation of EPSCs with BIC, the difference became statistically significant \(p<0.05, igure 2B, middle and )] TJ ET BT 26.250 45.974 Td /F1 9.8 Tf [(right graphs\). BIC reduced the frequency of synaptic currents in MSSNs from non-running WT animals, but in cells from running )] TJ ET Q q 15.000 31.688 577.500 745.312 re W n 0.965 0.965 0.965 rg 26.250 400.110 555.000 376.890 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 777.000 m 581.250 777.000 l 581.250 776.250 l 26.250 776.250 l f 26.250 400.110 m 581.250 400.110 l 581.250 400.860 l 26.250 400.860 l f q 153.000 0 0 225.000 35.250 542.250 cm /I3 Do Q q 35.250 411.360 537.000 124.890 re W n 0.271 0.267 0.267 rg BT 35.250 525.261 Td /F4 9.8 Tf [(Fig. 1:)] TJ ET BT 35.250 504.025 Td /F4 9.8 Tf [(A.)] TJ ET BT 45.000 504.025 Td /F1 9.8 Tf [( Examples of actograms from male and female WT \(left\) and R6/2 \(right\) mice during the light and dark cycles. R6/2 mice )] TJ ET BT 35.250 490.288 Td /F1 9.8 Tf [(displayed reduced activity compared to WTs. Each value represents the number of rotations per 3 min. The bars under the )] TJ ET BT 35.250 476.552 Td /F1 9.8 Tf [(actograms show the light and dark 12 h cycles. These actograms were obtained during the 3 days preceding the )] TJ ET BT 35.250 462.816 Td /F1 9.8 Tf [(electrophysiological recordings. The number of days in the running wheel cage is also indicated. )] TJ ET BT 451.975 462.816 Td /F4 9.8 Tf [(B)] TJ ET BT 459.014 462.816 Td /F1 9.8 Tf [(. Average activity during )] TJ ET BT 35.250 449.080 Td /F1 9.8 Tf [(the dark and light cycles. Throughout the duration of the experiment, R6/2 mice displayed lower levels of activity than WTs )] TJ ET BT 35.250 435.343 Td /F1 9.8 Tf [(in the dark. The differences were statistically significant \(p<0.01\) from the sixth day on \(indicated by the line and asterisks\). )] TJ ET BT 35.250 421.607 Td /F1 9.8 Tf [(There were no significant differences during the light cycle.)] TJ ET Q BT 26.250 383.086 Td /F1 9.8 Tf [(MSSNs from non-running transgenic mice had reduced membrane capacitance and increased input resistance compared to )] TJ ET BT 26.250 371.181 Td /F1 9.8 Tf [(WTs. These changes have been reported previously and probably indicate loss of cell membrane area )] TJ ET 0.267 0.267 0.267 rg BT 470.070 371.181 Td /F1 9.8 Tf [([8])] TJ ET BT 480.912 371.181 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 491.754 371.181 Td /F1 9.8 Tf [( as well as reduced )] TJ ET BT 26.250 359.277 Td /F1 9.8 Tf [(density of K )] TJ ET BT 79.904 363.165 Td /F1 8.7 Tf [(+)] TJ ET BT 84.966 359.277 Td /F1 9.8 Tf [( channels )] TJ ET 0.267 0.267 0.267 rg BT 129.406 359.277 Td /F1 9.8 Tf [([39])] TJ ET 0.271 0.267 0.267 rg BT 145.669 359.277 Td /F1 9.8 Tf [( . Running alleviated the significant difference in cell membrane capacitance between the groups )] TJ ET BT 26.250 347.372 Td /F1 9.8 Tf [(\(i.e., the difference between WT and R6/2 mice was no longer statistically significant\) \(Table 1\). In contrast, the increase in input )] TJ ET BT 26.250 335.467 Td /F1 9.8 Tf [(resistance in R6/2 mice was only slightly alleviated by exercise \(i.e., the magnitude of the increase in input resistance was )] TJ ET BT 26.250 323.562 Td /F1 9.8 Tf [(diminished but the difference between WT and R6/2 mice was still statistically significant\) \(Table 1\). The membrane time )] TJ ET BT 26.250 311.658 Td /F1 9.8 Tf [(constant \(t\) was not statistically different in the non-running or running groups \(Table 1\).)] TJ ET q 26.250 288.040 555.000 13.736 re W n 0.271 0.267 0.267 rg BT 26.250 290.788 Td /F1 9.8 Tf [(Table 1: Effects of Exercise on Basic Membrane Properties of MSSNs)] TJ ET Q 1.000 1.000 1.000 rg 26.250 203.236 555.000 77.305 re f 0.965 0.965 0.965 rg 27.000 267.511 188.337 12.280 re f 0.267 0.267 0.267 rg 26.625 279.415 188.712 0.750 re f 26.625 267.136 0.750 13.030 re f 0.965 0.965 0.965 rg 215.337 267.511 127.695 12.280 re f 0.267 0.267 0.267 rg 215.337 279.415 127.695 0.750 re f 0.271 0.267 0.267 rg BT 219.837 270.267 Td /F4 9.8 Tf [(Cm \(pF\))] TJ ET 0.965 0.965 0.965 rg 343.032 267.511 119.129 12.280 re f 0.267 0.267 0.267 rg 343.032 279.415 119.129 0.750 re f 0.271 0.267 0.267 rg BT 347.532 270.267 Td /F4 9.8 Tf [(Rm \(MO\))] TJ ET 0.965 0.965 0.965 rg 462.161 267.511 118.339 12.280 re f 0.267 0.267 0.267 rg 462.161 279.415 118.714 0.750 re f 580.125 267.136 0.750 13.030 re f 0.271 0.267 0.267 rg BT 466.661 270.267 Td /F4 9.8 Tf [(t \(ms\))] TJ ET 0.267 0.267 0.267 rg 26.625 267.136 189.087 0.750 re f 26.625 251.254 0.750 16.631 re f 0.271 0.267 0.267 rg BT 31.875 257.281 Td /F4 9.8 Tf [(WT Non-Running)] TJ ET 0.267 0.267 0.267 rg 214.962 267.136 128.445 0.750 re f 214.962 251.254 0.750 16.631 re f 0.271 0.267 0.267 rg BT 220.212 257.281 Td /F1 9.8 Tf [(83.44.1)] TJ ET 0.267 0.267 0.267 rg 342.657 267.136 119.879 0.750 re f 342.657 251.254 0.750 16.631 re f 0.271 0.267 0.267 rg BT 347.907 257.281 Td /F1 9.8 Tf [(727.2)] TJ ET 0.267 0.267 0.267 rg 461.786 267.136 119.089 0.750 re f 461.786 251.254 0.750 16.631 re f 580.125 251.254 0.750 16.631 re f 0.271 0.267 0.267 rg BT 467.036 257.281 Td /F1 9.8 Tf [(1.60.08)] TJ ET 0.267 0.267 0.267 rg 26.625 251.254 189.087 0.750 re f 26.625 235.373 0.750 16.631 re f 0.271 0.267 0.267 rg BT 31.875 241.399 Td /F4 9.8 Tf [(R6/2 Non-Running)] TJ ET 0.267 0.267 0.267 rg 214.962 251.254 128.445 0.750 re f 214.962 235.373 0.750 16.631 re f 0.271 0.267 0.267 rg BT 220.212 241.399 Td /F1 9.8 Tf [(70.33.6*)] TJ ET 0.267 0.267 0.267 rg 342.657 251.254 119.879 0.750 re f 342.657 235.373 0.750 16.631 re f 0.271 0.267 0.267 rg BT 347.907 241.399 Td /F1 9.8 Tf [(12616*)] TJ ET 0.267 0.267 0.267 rg 461.786 251.254 119.089 0.750 re f 461.786 235.373 0.750 16.631 re f 580.125 235.373 0.750 16.631 re f 0.271 0.267 0.267 rg BT 467.036 241.399 Td /F1 9.8 Tf [(1.40.06)] TJ ET 0.267 0.267 0.267 rg 26.625 235.373 189.087 0.750 re f 26.625 219.492 0.750 16.631 re f 0.271 0.267 0.267 rg BT 31.875 225.518 Td /F4 9.8 Tf [(WT Running)] TJ ET 0.267 0.267 0.267 rg 214.962 235.373 128.445 0.750 re f 214.962 219.492 0.750 16.631 re f 0.271 0.267 0.267 rg BT 220.212 225.518 Td /F1 9.8 Tf [(74.83.7)] TJ ET 0.267 0.267 0.267 rg 342.657 235.373 119.879 0.750 re f 342.657 219.492 0.750 16.631 re f 0.271 0.267 0.267 rg BT 347.907 225.518 Td /F1 9.8 Tf [(797.7)] TJ ET 0.267 0.267 0.267 rg 461.786 235.373 119.089 0.750 re f 461.786 219.492 0.750 16.631 re f 580.125 219.492 0.750 16.631 re f 0.271 0.267 0.267 rg BT 467.036 225.518 Td /F1 9.8 Tf [(1.40.07)] TJ ET 0.267 0.267 0.267 rg 26.625 219.492 189.087 0.750 re f 26.625 203.611 189.087 0.750 re f 26.625 203.611 0.750 16.631 re f 0.271 0.267 0.267 rg BT 31.875 209.637 Td /F4 9.8 Tf [(R6/2 Running)] TJ ET 0.267 0.267 0.267 rg 214.962 219.492 128.445 0.750 re f 214.962 203.611 128.445 0.750 re f 214.962 203.611 0.750 16.631 re f 0.271 0.267 0.267 rg BT 220.212 209.637 Td /F1 9.8 Tf [(84.13.6)] TJ ET 0.267 0.267 0.267 rg 342.657 219.492 119.879 0.750 re f 342.657 203.611 119.879 0.750 re f 342.657 203.611 0.750 16.631 re f 0.271 0.267 0.267 rg BT 347.907 209.637 Td /F1 9.8 Tf [(1097*)] TJ ET 0.267 0.267 0.267 rg 461.786 219.492 119.089 0.750 re f 461.786 203.611 119.089 0.750 re f 461.786 203.611 0.750 16.631 re f 580.125 203.611 0.750 16.631 re f 0.271 0.267 0.267 rg BT 467.036 209.637 Td /F1 9.8 Tf [(1.60.06)] TJ ET BT 26.250 148.712 Td /F1 9.8 Tf [(MSSNs from non-running transgenic mice had significantly reduced membrane capacitance \(Cm\) compared to WTs. Running )] TJ ET BT 26.250 136.807 Td /F1 9.8 Tf [(alleviated the significant difference in cell membrane capacitance between the groups. In contrast, the significant increase in )] TJ ET BT 26.250 124.902 Td /F1 9.8 Tf [(input resistance \(Rm\) in R6/2 mice was only partially alleviated by exercise. Time constant \(t\) was not significantly different in )] TJ ET BT 26.250 112.998 Td /F1 9.8 Tf [(non-running and running mice. Asterisks indicate the differences between WT and R6/2 mice were statistically significant.)] TJ ET BT 26.250 93.593 Td /F1 9.8 Tf [(Spontaneous EPSCs for all experiments were recorded at -70 mV holding potential. They were mediated by AMPA/kainate )] TJ ET BT 26.250 81.688 Td /F1 9.8 Tf [(glutamate receptors as they were almost completely abolished by CNQX, a non-NMDA receptor antagonist. Exercise produced )] TJ ET BT 26.250 69.783 Td /F1 9.8 Tf [(a non-significant increase in the frequency of spontaneous synaptic events in WT animals in ACSF \(Figure 2B, left graphs\). )] TJ ET BT 26.250 57.879 Td /F1 9.8 Tf [(After pharmacological isolation of EPSCs with BIC, the difference became statistically significant \(p<0.05, igure 2B, middle and )] TJ ET BT 26.250 45.974 Td /F1 9.8 Tf [(right graphs\). BIC reduced the frequency of synaptic currents in MSSNs from non-running WT animals, but in cells from running )] TJ ET Q q 15.000 31.688 577.500 745.312 re W n 0.965 0.965 0.965 rg 26.250 400.110 555.000 376.890 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 777.000 m 581.250 777.000 l 581.250 776.250 l 26.250 776.250 l f 26.250 400.110 m 581.250 400.110 l 581.250 400.860 l 26.250 400.860 l f q 153.000 0 0 225.000 35.250 542.250 cm /I3 Do Q q 35.250 411.360 537.000 124.890 re W n 0.271 0.267 0.267 rg BT 35.250 525.261 Td /F4 9.8 Tf [(Fig. 1:)] TJ ET BT 35.250 504.025 Td /F4 9.8 Tf [(A.)] TJ ET BT 45.000 504.025 Td /F1 9.8 Tf [( Examples of actograms from male and female WT \(left\) and R6/2 \(right\) mice during the light and dark cycles. R6/2 mice )] TJ ET BT 35.250 490.288 Td /F1 9.8 Tf [(displayed reduced activity compared to WTs. Each value represents the number of rotations per 3 min. The bars under the )] TJ ET BT 35.250 476.552 Td /F1 9.8 Tf [(actograms show the light and dark 12 h cycles. These actograms were obtained during the 3 days preceding the )] TJ ET BT 35.250 462.816 Td /F1 9.8 Tf [(electrophysiological recordings. The number of days in the running wheel cage is also indicated. )] TJ ET BT 451.975 462.816 Td /F4 9.8 Tf [(B)] TJ ET BT 459.014 462.816 Td /F1 9.8 Tf [(. Average activity during )] TJ ET BT 35.250 449.080 Td /F1 9.8 Tf [(the dark and light cycles. Throughout the duration of the experiment, R6/2 mice displayed lower levels of activity than WTs )] TJ ET BT 35.250 435.343 Td /F1 9.8 Tf [(in the dark. The differences were statistically significant \(p<0.01\) from the sixth day on \(indicated by the line and asterisks\). )] TJ ET BT 35.250 421.607 Td /F1 9.8 Tf [(There were no significant differences during the light cycle.)] TJ ET Q BT 26.250 383.086 Td /F1 9.8 Tf [(MSSNs from non-running transgenic mice had reduced membrane capacitance and increased input resistance compared to )] TJ ET BT 26.250 371.181 Td /F1 9.8 Tf [(WTs. These changes have been reported previously and probably indicate loss of cell membrane area )] TJ ET 0.267 0.267 0.267 rg BT 470.070 371.181 Td /F1 9.8 Tf [([8])] TJ ET BT 480.912 371.181 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 491.754 371.181 Td /F1 9.8 Tf [( as well as reduced )] TJ ET BT 26.250 359.277 Td /F1 9.8 Tf [(density of K )] TJ ET BT 79.904 363.165 Td /F1 8.7 Tf [(+)] TJ ET BT 84.966 359.277 Td /F1 9.8 Tf [( channels )] TJ ET 0.267 0.267 0.267 rg BT 129.406 359.277 Td /F1 9.8 Tf [([39])] TJ ET 0.271 0.267 0.267 rg BT 145.669 359.277 Td /F1 9.8 Tf [( . Running alleviated the significant difference in cell membrane capacitance between the groups )] TJ ET BT 26.250 347.372 Td /F1 9.8 Tf [(\(i.e., the difference between WT and R6/2 mice was no longer statistically significant\) \(Table 1\). In contrast, the increase in input )] TJ ET BT 26.250 335.467 Td /F1 9.8 Tf [(resistance in R6/2 mice was only slightly alleviated by exercise \(i.e., the magnitude of the increase in input resistance was )] TJ ET BT 26.250 323.562 Td /F1 9.8 Tf [(diminished but the difference between WT and R6/2 mice was still statistically significant\) \(Table 1\). The membrane time )] TJ ET BT 26.250 311.658 Td /F1 9.8 Tf [(constant \(t\) was not statistically different in the non-running or running groups \(Table 1\).)] TJ ET q 26.250 288.040 555.000 13.736 re W n 0.271 0.267 0.267 rg BT 26.250 290.788 Td /F1 9.8 Tf [(Table 1: Effects of Exercise on Basic Membrane Properties of MSSNs)] TJ ET Q 1.000 1.000 1.000 rg 26.250 203.236 555.000 77.305 re f 0.965 0.965 0.965 rg 27.000 267.511 188.337 12.280 re f 0.267 0.267 0.267 rg 26.625 279.415 188.712 0.750 re f 26.625 267.136 0.750 13.030 re f 0.965 0.965 0.965 rg 215.337 267.511 127.695 12.280 re f 0.267 0.267 0.267 rg 215.337 279.415 127.695 0.750 re f 0.271 0.267 0.267 rg BT 219.837 270.267 Td /F4 9.8 Tf [(Cm \(pF\))] TJ ET 0.965 0.965 0.965 rg 343.032 267.511 119.129 12.280 re f 0.267 0.267 0.267 rg 343.032 279.415 119.129 0.750 re f 0.271 0.267 0.267 rg BT 347.532 270.267 Td /F4 9.8 Tf [(Rm \(MO\))] TJ ET 0.965 0.965 0.965 rg 462.161 267.511 118.339 12.280 re f 0.267 0.267 0.267 rg 462.161 279.415 118.714 0.750 re f 580.125 267.136 0.750 13.030 re f 0.271 0.267 0.267 rg BT 466.661 270.267 Td /F4 9.8 Tf [(t \(ms\))] TJ ET 0.267 0.267 0.267 rg 26.625 267.136 189.087 0.750 re f 26.625 251.254 0.750 16.631 re f 0.271 0.267 0.267 rg BT 31.875 257.281 Td /F4 9.8 Tf [(WT Non-Running)] TJ ET 0.267 0.267 0.267 rg 214.962 267.136 128.445 0.750 re f 214.962 251.254 0.750 16.631 re f 0.271 0.267 0.267 rg BT 220.212 257.281 Td /F1 9.8 Tf [(83.44.1)] TJ ET 0.267 0.267 0.267 rg 342.657 267.136 119.879 0.750 re f 342.657 251.254 0.750 16.631 re f 0.271 0.267 0.267 rg BT 347.907 257.281 Td /F1 9.8 Tf [(727.2)] TJ ET 0.267 0.267 0.267 rg 461.786 267.136 119.089 0.750 re f 461.786 251.254 0.750 16.631 re f 580.125 251.254 0.750 16.631 re f 0.271 0.267 0.267 rg BT 467.036 257.281 Td /F1 9.8 Tf [(1.60.08)] TJ ET 0.267 0.267 0.267 rg 26.625 251.254 189.087 0.750 re f 26.625 235.373 0.750 16.631 re f 0.271 0.267 0.267 rg BT 31.875 241.399 Td /F4 9.8 Tf [(R6/2 Non-Running)] TJ ET 0.267 0.267 0.267 rg 214.962 251.254 128.445 0.750 re f 214.962 235.373 0.750 16.631 re f 0.271 0.267 0.267 rg BT 220.212 241.399 Td /F1 9.8 Tf [(70.33.6*)] TJ ET 0.267 0.267 0.267 rg 342.657 251.254 119.879 0.750 re f 342.657 235.373 0.750 16.631 re f 0.271 0.267 0.267 rg BT 347.907 241.399 Td /F1 9.8 Tf [(12616*)] TJ ET 0.267 0.267 0.267 rg 461.786 251.254 119.089 0.750 re f 461.786 235.373 0.750 16.631 re f 580.125 235.373 0.750 16.631 re f 0.271 0.267 0.267 rg BT 467.036 241.399 Td /F1 9.8 Tf [(1.40.06)] TJ ET 0.267 0.267 0.267 rg 26.625 235.373 189.087 0.750 re f 26.625 219.492 0.750 16.631 re f 0.271 0.267 0.267 rg BT 31.875 225.518 Td /F4 9.8 Tf [(WT Running)] TJ ET 0.267 0.267 0.267 rg 214.962 235.373 128.445 0.750 re f 214.962 219.492 0.750 16.631 re f 0.271 0.267 0.267 rg BT 220.212 225.518 Td /F1 9.8 Tf [(74.83.7)] TJ ET 0.267 0.267 0.267 rg 342.657 235.373 119.879 0.750 re f 342.657 219.492 0.750 16.631 re f 0.271 0.267 0.267 rg BT 347.907 225.518 Td /F1 9.8 Tf [(797.7)] TJ ET 0.267 0.267 0.267 rg 461.786 235.373 119.089 0.750 re f 461.786 219.492 0.750 16.631 re f 580.125 219.492 0.750 16.631 re f 0.271 0.267 0.267 rg BT 467.036 225.518 Td /F1 9.8 Tf [(1.40.07)] TJ ET 0.267 0.267 0.267 rg 26.625 219.492 189.087 0.750 re f 26.625 203.611 189.087 0.750 re f 26.625 203.611 0.750 16.631 re f 0.271 0.267 0.267 rg BT 31.875 209.637 Td /F4 9.8 Tf [(R6/2 Running)] TJ ET 0.267 0.267 0.267 rg 214.962 219.492 128.445 0.750 re f 214.962 203.611 128.445 0.750 re f 214.962 203.611 0.750 16.631 re f 0.271 0.267 0.267 rg BT 220.212 209.637 Td /F1 9.8 Tf [(84.13.6)] TJ ET 0.267 0.267 0.267 rg 342.657 219.492 119.879 0.750 re f 342.657 203.611 119.879 0.750 re f 342.657 203.611 0.750 16.631 re f 0.271 0.267 0.267 rg BT 347.907 209.637 Td /F1 9.8 Tf [(1097*)] TJ ET 0.267 0.267 0.267 rg 461.786 219.492 119.089 0.750 re f 461.786 203.611 119.089 0.750 re f 461.786 203.611 0.750 16.631 re f 580.125 203.611 0.750 16.631 re f 0.271 0.267 0.267 rg BT 467.036 209.637 Td /F1 9.8 Tf [(1.60.06)] TJ ET BT 26.250 148.712 Td /F1 9.8 Tf [(MSSNs from non-running transgenic mice had significantly reduced membrane capacitance \(Cm\) compared to WTs. Running )] TJ ET BT 26.250 136.807 Td /F1 9.8 Tf [(alleviated the significant difference in cell membrane capacitance between the groups. In contrast, the significant increase in )] TJ ET BT 26.250 124.902 Td /F1 9.8 Tf [(input resistance \(Rm\) in R6/2 mice was only partially alleviated by exercise. Time constant \(t\) was not significantly different in )] TJ ET BT 26.250 112.998 Td /F1 9.8 Tf [(non-running and running mice. Asterisks indicate the differences between WT and R6/2 mice were statistically significant.)] TJ ET BT 26.250 93.593 Td /F1 9.8 Tf [(Spontaneous EPSCs for all experiments were recorded at -70 mV holding potential. They were mediated by AMPA/kainate )] TJ ET BT 26.250 81.688 Td /F1 9.8 Tf [(glutamate receptors as they were almost completely abolished by CNQX, a non-NMDA receptor antagonist. Exercise produced )] TJ ET BT 26.250 69.783 Td /F1 9.8 Tf [(a non-significant increase in the frequency of spontaneous synaptic events in WT animals in ACSF \(Figure 2B, left graphs\). )] TJ ET BT 26.250 57.879 Td /F1 9.8 Tf [(After pharmacological isolation of EPSCs with BIC, the difference became statistically significant \(p<0.05, igure 2B, middle and )] TJ ET BT 26.250 45.974 Td /F1 9.8 Tf [(right graphs\). BIC reduced the frequency of synaptic currents in MSSNs from non-running WT animals, but in cells from running )] TJ ET Q q 153.000 0 0 225.000 35.250 542.250 cm /I3 Do Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(4)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 345 0 obj << /Type /Annot /Subtype /Link /A 346 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 542.2500 188.2500 767.2500 ] >> endobj 346 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2010/09/fig01.tif) >> endobj 347 0 obj << /Type /XObject /Subtype /Image /Width 204 /Height 300 /ColorSpace /DeviceRGB /Filter /DCTDecode /BitsPerComponent 8 /Length 18342>> stream JFIF;CREATOR: gd-jpeg v1.0 (using IJG JPEG v62), quality = 90 C     C   ," }!1AQa"q2#BR$3br %&'()*456789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz w!1AQaq"2B #3Rbr $4%&'()*56789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz ?ï'޽MawQm`S)0Deq7<Ȋ-?)k4jw^N;4|Nd%Y{U=l,2P2юy׆#rɛư\&p3b3sU@;>i5Εw, '3Qi^(ޙiwwq,ʯS̙ߵq>1H|  \/<7nu;HeRYE e9(?. }}hպ-*(ϼU[OxO/tTMfy %PXR<46Ii֑kUq : w_,ݔy1@5s|U#Ym$Istœ7¾-nӬPslkv5Q8%Z?Uq> \]ѾI fS[1^s@[;ZTPoo?ڷ_ПW+}hbc`9FAwz&XV "ɍCqVvm~dl(0A جۏ,C[p?n {}kK4Poo?ڷ_㵥Ext3Ce3\ ҫ'! 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This increase encompassed both small \(5-20 pA\) and large \(>20 )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(pA\) amplitude synaptic events. In contrast, in R6/2 mice the reduced levels of spontaneous synaptic currents were not )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(enhanced by exercise in either condition. There was a trend, however, for BIC to produce a smaller decrease in the R6/2 mice )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(in the running wheel \(Figure 2B, right graph\). It is tempting to speculate that the general lack of effectiveness of exercise was )] TJ ET BT 26.250 719.857 Td /F1 9.8 Tf [(due to the fact that R6/2 mice displayed reduced levels of physical activity even at a very young age.)] TJ ET 0.965 0.965 0.965 rg 26.250 319.350 555.000 390.626 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 709.976 m 581.250 709.976 l 581.250 709.226 l 26.250 709.226 l f 26.250 319.350 m 581.250 319.350 l 581.250 320.100 l 26.250 320.100 l f q 218.250 0 0 225.000 35.250 475.226 cm /I4 Do Q q 35.250 330.600 537.000 138.626 re W n 0.271 0.267 0.267 rg BT 35.250 458.237 Td /F4 9.8 Tf [(Fig. 2:)] TJ ET BT 35.250 437.001 Td /F4 9.8 Tf [(A.)] TJ ET BT 45.000 437.001 Td /F1 9.8 Tf [( Traces show spontaneous synaptic currents before \(ACSF\) and after bicuculline application \(BIC, 10 M\) to isolate )] TJ ET BT 35.250 423.265 Td /F1 9.8 Tf [(EPSCs in MSSNs from WT and R6/2 mice \(V)] TJ ET BT 230.835 422.116 Td /F1 8.7 Tf [(h)] TJ ET BT 235.654 423.265 Td /F1 9.8 Tf [(=holding voltage\). In both conditions, MSSNs from running WT mice )] TJ ET BT 35.250 409.528 Td /F1 9.8 Tf [(displayed more spontaneous synaptic currents encompassing both small and large amplitude events. )] TJ ET BT 474.195 409.528 Td /F4 9.8 Tf [(B.)] TJ ET BT 483.945 409.528 Td /F1 9.8 Tf [( Graphs show )] TJ ET BT 35.250 395.792 Td /F1 9.8 Tf [(average frequency of spontaneous EPSCs \(in Hz\) in MSSNs from running and non-running WT and R6/2 mice. The )] TJ ET BT 35.250 382.056 Td /F1 9.8 Tf [(frequency of EPSCs was significantly reduced in R6/2 compared to WTs. After isolation of EPSCs with BIC, the average )] TJ ET BT 35.250 368.320 Td /F1 9.8 Tf [(frequency of spontaneous events was significantly increased in running WT mice. While BIC reduced the number of )] TJ ET BT 35.250 354.583 Td /F1 9.8 Tf [(spontaneous events in the other three groups, it significantly increased the frequency of spontaneous events in running WT )] TJ ET BT 35.250 340.847 Td /F1 9.8 Tf [(mice. Significant differences \(p<0.05\) are indicated by asterisks.)] TJ ET Q BT 26.250 302.326 Td /F1 9.8 Tf [(Exercise also affected the kinetics of spontaneous EPSCs in MSSNs from running compared to non-running WT mice \(Figure )] TJ ET BT 26.250 290.421 Td /F1 9.8 Tf [(3\). Although decay times and half-amplitude durations were similar, the rise times were significantly faster in cells from WT )] TJ ET BT 26.250 278.517 Td /F1 9.8 Tf [(running mice \(Figure 3B\). In cells from running R6/2 mice there also was a trend towards faster rise times, but the difference did )] TJ ET BT 26.250 266.612 Td /F1 9.8 Tf [(not reach statistical significance \(p=0.07\). Average event amplitudes were not significantly different among groups \(data not )] TJ ET BT 26.250 254.707 Td /F1 9.8 Tf [(shown\).)] TJ ET 0.965 0.965 0.965 rg 26.250 4.076 555.000 240.750 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 244.826 m 581.250 244.826 l 581.250 244.076 l 26.250 244.076 l f q 222.750 0 0 225.000 35.250 10.076 cm /I5 Do Q q 35.250 4.076 537.000 0.000 re W n Q Q q 15.000 4.076 577.500 772.924 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(animals the frequency of spontaneous EPSCs was increased. This increase encompassed both small \(5-20 pA\) and large \(>20 )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(pA\) amplitude synaptic events. In contrast, in R6/2 mice the reduced levels of spontaneous synaptic currents were not )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(enhanced by exercise in either condition. There was a trend, however, for BIC to produce a smaller decrease in the R6/2 mice )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(in the running wheel \(Figure 2B, right graph\). It is tempting to speculate that the general lack of effectiveness of exercise was )] TJ ET BT 26.250 719.857 Td /F1 9.8 Tf [(due to the fact that R6/2 mice displayed reduced levels of physical activity even at a very young age.)] TJ ET 0.965 0.965 0.965 rg 26.250 319.350 555.000 390.626 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 709.976 m 581.250 709.976 l 581.250 709.226 l 26.250 709.226 l f 26.250 319.350 m 581.250 319.350 l 581.250 320.100 l 26.250 320.100 l f q 218.250 0 0 225.000 35.250 475.226 cm /I4 Do Q q 35.250 330.600 537.000 138.626 re W n 0.271 0.267 0.267 rg BT 35.250 458.237 Td /F4 9.8 Tf [(Fig. 2:)] TJ ET BT 35.250 437.001 Td /F4 9.8 Tf [(A.)] TJ ET BT 45.000 437.001 Td /F1 9.8 Tf [( Traces show spontaneous synaptic currents before \(ACSF\) and after bicuculline application \(BIC, 10 M\) to isolate )] TJ ET BT 35.250 423.265 Td /F1 9.8 Tf [(EPSCs in MSSNs from WT and R6/2 mice \(V)] TJ ET BT 230.835 422.116 Td /F1 8.7 Tf [(h)] TJ ET BT 235.654 423.265 Td /F1 9.8 Tf [(=holding voltage\). In both conditions, MSSNs from running WT mice )] TJ ET BT 35.250 409.528 Td /F1 9.8 Tf [(displayed more spontaneous synaptic currents encompassing both small and large amplitude events. )] TJ ET BT 474.195 409.528 Td /F4 9.8 Tf [(B.)] TJ ET BT 483.945 409.528 Td /F1 9.8 Tf [( Graphs show )] TJ ET BT 35.250 395.792 Td /F1 9.8 Tf [(average frequency of spontaneous EPSCs \(in Hz\) in MSSNs from running and non-running WT and R6/2 mice. The )] TJ ET BT 35.250 382.056 Td /F1 9.8 Tf [(frequency of EPSCs was significantly reduced in R6/2 compared to WTs. After isolation of EPSCs with BIC, the average )] TJ ET BT 35.250 368.320 Td /F1 9.8 Tf [(frequency of spontaneous events was significantly increased in running WT mice. While BIC reduced the number of )] TJ ET BT 35.250 354.583 Td /F1 9.8 Tf [(spontaneous events in the other three groups, it significantly increased the frequency of spontaneous events in running WT )] TJ ET BT 35.250 340.847 Td /F1 9.8 Tf [(mice. Significant differences \(p<0.05\) are indicated by asterisks.)] TJ ET Q BT 26.250 302.326 Td /F1 9.8 Tf [(Exercise also affected the kinetics of spontaneous EPSCs in MSSNs from running compared to non-running WT mice \(Figure )] TJ ET BT 26.250 290.421 Td /F1 9.8 Tf [(3\). Although decay times and half-amplitude durations were similar, the rise times were significantly faster in cells from WT )] TJ ET BT 26.250 278.517 Td /F1 9.8 Tf [(running mice \(Figure 3B\). In cells from running R6/2 mice there also was a trend towards faster rise times, but the difference did )] TJ ET BT 26.250 266.612 Td /F1 9.8 Tf [(not reach statistical significance \(p=0.07\). Average event amplitudes were not significantly different among groups \(data not )] TJ ET BT 26.250 254.707 Td /F1 9.8 Tf [(shown\).)] TJ ET 0.965 0.965 0.965 rg 26.250 4.076 555.000 240.750 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 244.826 m 581.250 244.826 l 581.250 244.076 l 26.250 244.076 l f q 222.750 0 0 225.000 35.250 10.076 cm /I5 Do Q q 35.250 4.076 537.000 0.000 re W n Q Q q 15.000 4.076 577.500 772.924 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(animals the frequency of spontaneous EPSCs was increased. This increase encompassed both small \(5-20 pA\) and large \(>20 )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(pA\) amplitude synaptic events. In contrast, in R6/2 mice the reduced levels of spontaneous synaptic currents were not )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(enhanced by exercise in either condition. There was a trend, however, for BIC to produce a smaller decrease in the R6/2 mice )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(in the running wheel \(Figure 2B, right graph\). It is tempting to speculate that the general lack of effectiveness of exercise was )] TJ ET BT 26.250 719.857 Td /F1 9.8 Tf [(due to the fact that R6/2 mice displayed reduced levels of physical activity even at a very young age.)] TJ ET 0.965 0.965 0.965 rg 26.250 319.350 555.000 390.626 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 709.976 m 581.250 709.976 l 581.250 709.226 l 26.250 709.226 l f 26.250 319.350 m 581.250 319.350 l 581.250 320.100 l 26.250 320.100 l f q 218.250 0 0 225.000 35.250 475.226 cm /I4 Do Q q 35.250 330.600 537.000 138.626 re W n 0.271 0.267 0.267 rg BT 35.250 458.237 Td /F4 9.8 Tf [(Fig. 2:)] TJ ET BT 35.250 437.001 Td /F4 9.8 Tf [(A.)] TJ ET BT 45.000 437.001 Td /F1 9.8 Tf [( Traces show spontaneous synaptic currents before \(ACSF\) and after bicuculline application \(BIC, 10 M\) to isolate )] TJ ET BT 35.250 423.265 Td /F1 9.8 Tf [(EPSCs in MSSNs from WT and R6/2 mice \(V)] TJ ET BT 230.835 422.116 Td /F1 8.7 Tf [(h)] TJ ET BT 235.654 423.265 Td /F1 9.8 Tf [(=holding voltage\). In both conditions, MSSNs from running WT mice )] TJ ET BT 35.250 409.528 Td /F1 9.8 Tf [(displayed more spontaneous synaptic currents encompassing both small and large amplitude events. )] TJ ET BT 474.195 409.528 Td /F4 9.8 Tf [(B.)] TJ ET BT 483.945 409.528 Td /F1 9.8 Tf [( Graphs show )] TJ ET BT 35.250 395.792 Td /F1 9.8 Tf [(average frequency of spontaneous EPSCs \(in Hz\) in MSSNs from running and non-running WT and R6/2 mice. The )] TJ ET BT 35.250 382.056 Td /F1 9.8 Tf [(frequency of EPSCs was significantly reduced in R6/2 compared to WTs. After isolation of EPSCs with BIC, the average )] TJ ET BT 35.250 368.320 Td /F1 9.8 Tf [(frequency of spontaneous events was significantly increased in running WT mice. While BIC reduced the number of )] TJ ET BT 35.250 354.583 Td /F1 9.8 Tf [(spontaneous events in the other three groups, it significantly increased the frequency of spontaneous events in running WT )] TJ ET BT 35.250 340.847 Td /F1 9.8 Tf [(mice. Significant differences \(p<0.05\) are indicated by asterisks.)] TJ ET Q BT 26.250 302.326 Td /F1 9.8 Tf [(Exercise also affected the kinetics of spontaneous EPSCs in MSSNs from running compared to non-running WT mice \(Figure )] TJ ET BT 26.250 290.421 Td /F1 9.8 Tf [(3\). Although decay times and half-amplitude durations were similar, the rise times were significantly faster in cells from WT )] TJ ET BT 26.250 278.517 Td /F1 9.8 Tf [(running mice \(Figure 3B\). In cells from running R6/2 mice there also was a trend towards faster rise times, but the difference did )] TJ ET BT 26.250 266.612 Td /F1 9.8 Tf [(not reach statistical significance \(p=0.07\). Average event amplitudes were not significantly different among groups \(data not )] TJ ET BT 26.250 254.707 Td /F1 9.8 Tf [(shown\).)] TJ ET 0.965 0.965 0.965 rg 26.250 4.076 555.000 240.750 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 244.826 m 581.250 244.826 l 581.250 244.076 l 26.250 244.076 l f q 222.750 0 0 225.000 35.250 10.076 cm /I5 Do Q q 35.250 4.076 537.000 0.000 re W n Q Q q 218.250 0 0 225.000 35.250 475.226 cm /I4 Do Q q 222.750 0 0 225.000 35.250 10.076 cm /I5 Do Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(5)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 372 0 obj << /Type /Annot /Subtype /Link /A 373 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 475.2262 253.5000 700.2262 ] >> endobj 373 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2010/09/fig02.tif) >> endobj 374 0 obj << /Type /XObject /Subtype /Image /Width 291 /Height 300 /ColorSpace /DeviceRGB /Filter /DCTDecode /BitsPerComponent 8 /Length 23133>> stream JFIF;CREATOR: gd-jpeg v1.0 (using IJG JPEG v62), quality = 90 C     C   ,#" }!1AQa"q2#BR$3br %&'()*456789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz w!1AQaq"2B #3Rbr $4%&'()*56789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz ?ᖃ F/O4oY_E̯wioKH+/ sx&j6SO]V6y\:J Wg=0N+T%T˒-M4泼FֿRcv.]٥OGeL6I>xhúb8žq3Q^oØmD r2rV~П>yIZ f+< c)sq)0B>U2(⼇ߵvV9.x-@щ$fJ;gΐtkS~y<|GS-# Hw[I01q~G}mh|}y v''$:n+h.LeIbCo\|ߴ/ya2lj,[n@ƣoww =Ă4RHP @Vsq$ -aF^CyU.wqA# gI=[=GǺ+[>ǩ!qv[IG 3a5 [O⍽蚥 ;1'F=^koIJpJS4Ko7RiecԯSa4 /W0IbSkveTc;g9S?Ljvޯ=n1skkF8I yeDms@-y>[Կ? ZŔO0rK1d1*01/$MGg_7>~M-@*3@\2V$psA&} _ ˯jkotF !%?qF9ѻb+ZQk8%0.Fr'=8N){>MKR.o5(-e\o\Hd)ך'IjvxRkF8~d9 ־4}RwK#C2Vr( x BѠ՞y.mm%(n!pJ;VKOe,I'wmx[e.A1]o*.v?R P>wixS6\O#n9$l08dvOsOi)'U}a= }:kI,[A5cB[m77?1Es Qp pǮEs~!~? 9C>Q3ʱ0Sd_%oA^(0* u iX<3-N'4p  ?03~GؑY7,W'(5_EP;P#,?U{ MurcH8VuP Ո {q[#> ^V}SidF)Py01^84C?8dtmWRVWNbc9$H' ,wq>,YQt <ܞ6+~hkjmt]Dԅy~=W[#aF\s֮Ucז[nP!۴ st=4gZiz#HGXh:&,zv{MmZHUr9{Ԟ3}*iV:-9mRK(0y< }{63Dg$#g_D'dn Tg_>~ ]zxrKF0HL~\aw `W_« JOBk#nId+ס@{\bx}gt蚽*)/m![|d#rr. so[xnͼfBNHavlg} E|?+8td;}<(8ޣ|o̭Y\#r3qs^GzثKM: ) 2!'?. 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Jې~!EU"D#w[Tߺn{O Ij_*O?t6Pu/?ֿF?k<%^Wd?TқZhypPx[GO wNҸk:xWúw_?}_E%zGKG_Jm?k9?I^/қz #)~y&># F\F#7-e1mG FoZJc_ȇݟ#|LJ)+?%s:3dKb }$ו57Q}F6Ic2[ 2B$RCͻ(\`cdY啂'@=|IRҩ+M_0__ͯǸiF)$<&0ϝ?P+jݸJ;4Eԭ3N$_0_@|EPҙ+&/>; oǛk)b:# ĄGQ_H5u3IwQW n'X1d_eo/ɟڼ_Z:QRWt4D|qt=?eU\|OH cȵ]tdMsAbx4_<.X-,r澮ioWOֹ?$W nٗ'P  z~5o ål_UAo%hȑ_J*T6albso*W?t6W'^J#)ֿmwp7r.4`pːpAz'NXRJmkc_y_GM.l|-vk"BԁjO_­kX*Y݆1\%p}yVqW/ zjxڅkz{3D@+N5CT;\J&ؿ'׏~շpjW-fKRXX20G_ ɫX|A6{och2"s*ƥ,G<ʿ7F_-K?3oǏ l?6j4!x_Stldq\f=!/m~}"obh,2QP#Z(k±[\kqkoyy I.# !e'8ڲ~#j^(ҬZ#,ȣU7d62W+ּ/ kšvumZ.H$0In< Ž?,~ẖ换 H,$+rz_?%xIJFe(TULN%yg긯 exP/kEL +XTBH]t9;']Zi5̦mv0aц_5S۠ҾLP̏6`)1,o[`_jG]@Ezdkr(QifT~Rd {> χ'1 ̉,` Ì@ [мu{=R &Y!̑K1^jF0Hg|C־ ~&xoL (,f(7rqenx^vkwu2*0*|ف7?hү%-.dK NNo\p~F\.Tf[ZԯgaGԓ|ǧ^j()3-+xNO ie;S*I:*xbH.&Xk+mzO0w xeeUjǷ!3 /2Ëܨn#rQH,MxSĞ,5{%bhw\=3⟝|!2:k !4&$1`Hq)B%׋5 nCgV%o+.;blccsw~4wԵ;8f1iK1Bq%bs`+sos5ţ$PNARP;E'k{oŬ[idRǨVTܵ6FLD;)i6]r Vߜe\*@fr^?yo +RCŸ6U;w̅\dQqSյN L,*H݂y@B~~<'Wt|+EG^'&URXr gRxg߲ڎ}%7 ݈> ^'L[SJfS yFm(p+ X}5^KRdGn"V"zn' ]\xz/5d)[>Yu :X_-xǀGzPK,d#NrXQ" ag׾ivs&`d -9`Oygek__E?Vf-"@YFNq$2qv~ k,RkkmZ{8m+݂rF>?q<cAl=te2z8 Ђ #KkyH̊YB]F x'{߉MoPMjYK$(,r8fV*d>"񷈼Exr]v3ng%rd7l}p ı{}_Zj3EayLaFAC\l}QΖs v<̀A89[<^}u)tyR 6(6!)Ѫ^JHIPX~ fyiⷖ;wn73y*2 :d|5cPO_hr$ź`#I&h endstream endobj 378 0 obj << /Type /Annot /Subtype /Link /A 379 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 475.2262 253.5000 700.2262 ] >> endobj 379 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2010/09/fig02.tif) >> endobj 380 0 obj << /Type /Annot /Subtype /Link /A 381 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 10.0762 258.0000 235.0762 ] >> endobj 381 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2010/09/fig03.tif) >> endobj 382 0 obj << /Type /Annot /Subtype /Link /A 383 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 475.2262 253.5000 700.2262 ] >> endobj 383 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2010/09/fig02.tif) >> endobj 384 0 obj << /Type /Annot /Subtype /Link /A 385 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 10.0762 258.0000 235.0762 ] >> endobj 385 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2010/09/fig03.tif) >> endobj 386 0 obj << /Type /Page /Parent 3 0 R /Annots [ 388 0 R 390 0 R 393 0 R 395 0 R 397 0 R 399 0 R ] /Contents 387 0 R >> endobj 387 0 obj << /Length 15042 >> stream q 15.000 54.570 577.500 722.430 re W n 0.965 0.965 0.965 rg 26.250 695.805 555.000 81.195 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 695.805 m 581.250 695.805 l 581.250 696.555 l 26.250 696.555 l f q 35.250 707.055 537.000 69.945 re W n 0.271 0.267 0.267 rg BT 35.250 766.011 Td /F4 9.8 Tf [(Fig. 3:)] TJ ET BT 35.250 744.775 Td /F4 9.8 Tf [(A.)] TJ ET BT 45.000 744.775 Td /F1 9.8 Tf [( Traces are averages of spontaneous EPSCs \(10-50 pA\) in MSSNs from running and non-running WT and R6/2 animals. )] TJ ET BT 35.250 731.038 Td /F1 9.8 Tf [(No significant differences in amplitude \(not shown\), decay time or half-amplitude duration were found. However, the rise )] TJ ET BT 35.250 717.302 Td /F1 9.8 Tf [(time was significantly shorter \(p=0.005\) in running compared to non-running WT mice.)] TJ ET Q BT 26.250 678.781 Td /F1 9.8 Tf [(BDNF protein content in non-running and running WT and R6/2 mice was determined biochemically using ELISA. At the ages )] TJ ET BT 26.250 666.876 Td /F1 9.8 Tf [(examined \(average 60 days\), no statistically significant differences in BDNF content were found among groups. There was a )] TJ ET BT 26.250 654.972 Td /F1 9.8 Tf [(small trend for higher BDNF in WT \(9.991.2 pg/g\) compared to R6/2 \(8.311.4 pg/g\) non-running mice and in WT \(9.941.5 )] TJ ET BT 26.250 643.067 Td /F1 9.8 Tf [(pg/g\) versus R6/2 \(8.690.4 pg/g\) running mice but the differences were not large enough to reach statistical significance. )] TJ ET BT 26.250 631.162 Td /F1 9.8 Tf [(Exercise did not change BDNF levels in WT or R6/2 mice indicating that running )] TJ ET BT 374.130 631.162 Td /F5 9.8 Tf [(per se)] TJ ET BT 401.225 631.162 Td /F1 9.8 Tf [( does not increase striatal BDNF content.)] TJ ET BT 26.250 611.757 Td /F4 9.8 Tf [(Adenosine:)] TJ ET BT 26.250 592.353 Td /F1 9.8 Tf [(The first adenosine receptor modulator we tested was KW 6002, a selective A)] TJ ET BT 361.689 590.288 Td /F1 8.7 Tf [(2A)] TJ ET BT 372.288 592.353 Td /F1 9.8 Tf [( receptor-antagonist. The effects of this )] TJ ET BT 26.250 580.448 Td /F1 9.8 Tf [(compound on spontaneous synaptic activity were inconsistent with cells displaying both increases and decreases in frequency )] TJ ET BT 26.250 568.543 Td /F1 9.8 Tf [(\(data not shown\), although proportionately more cells \(6/10\) from R6/2 mice showed increases in frequency compared to WT )] TJ ET BT 26.250 556.638 Td /F1 9.8 Tf [(cells \(2/9\). As A)] TJ ET BT 94.519 554.574 Td /F1 8.7 Tf [(2A)] TJ ET BT 105.119 556.638 Td /F1 9.8 Tf [( receptors are segregated in striatum, it was possible that the lack of consistency was due to recording from )] TJ ET BT 26.250 544.734 Td /F1 9.8 Tf [(different cell populations originating the direct \(non-A)] TJ ET BT 253.854 542.669 Td /F1 8.7 Tf [(2A)] TJ ET BT 264.453 544.734 Td /F1 9.8 Tf [( receptor-expressing\) or indirect \(A)] TJ ET BT 414.535 542.669 Td /F1 8.7 Tf [(2A)] TJ ET BT 425.134 544.734 Td /F1 9.8 Tf [( or D2 receptor-expressing\) )] TJ ET BT 26.250 532.829 Td /F1 9.8 Tf [(pathways. In consequence, we also used WT mice expressing EGFP in A)] TJ ET BT 343.798 530.765 Td /F1 8.7 Tf [(2A)] TJ ET BT 354.397 532.829 Td /F1 9.8 Tf [( adenosine or D2 dopamine receptor-containing )] TJ ET BT 26.250 520.924 Td /F1 9.8 Tf [(MSSNs. Again both increases and decreases were observed. However, more cells displayed decreases in frequency, in )] TJ ET BT 26.250 509.019 Td /F1 9.8 Tf [(agreement with the effects observed in unidentified WT MSSNs.)] TJ ET BT 26.250 489.615 Td /F1 9.8 Tf [(As previous evidence indicated that the same adenosine modulators could have differential effects on NMDA receptor-mediated )] TJ ET BT 26.250 477.710 Td /F1 9.8 Tf [(responses in WT and R6/2 mice )] TJ ET 0.267 0.267 0.267 rg BT 167.674 477.710 Td /F1 9.8 Tf [([26])] TJ ET 0.271 0.267 0.267 rg BT 183.937 477.710 Td /F1 9.8 Tf [( , we tested the effects of an A)] TJ ET BT 315.104 475.646 Td /F1 8.7 Tf [(2A)] TJ ET BT 325.703 477.710 Td /F1 9.8 Tf [( receptor agonist, CGS 21680. Indeed, this agonist )] TJ ET BT 26.250 465.805 Td /F1 9.8 Tf [(produced contrasting effects in MSSNs from WT and R6/2 mice. In WT mice the agonist produced small decreases in average )] TJ ET BT 26.250 453.900 Td /F1 9.8 Tf [(frequency of events whereas in cells from R6/2 mice it increased the frequency of spontaneous EPSCs \(Figure 4A, B\). )] TJ ET BT 26.250 441.996 Td /F1 9.8 Tf [(Cumulative inter-event histograms showed that CGS 21680 renormalized EPSC frequency in that there were fewer statistically )] TJ ET BT 26.250 430.091 Td /F1 9.8 Tf [(significant inter-event interval bin differences \(Figure 4C\).)] TJ ET 0.965 0.965 0.965 rg 26.250 54.570 555.000 365.640 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 420.210 m 581.250 420.210 l 581.250 419.460 l 26.250 419.460 l f q 221.250 0 0 225.000 35.250 185.460 cm /I6 Do Q q 35.250 54.570 537.000 124.890 re W n Q Q q 15.000 54.570 577.500 722.430 re W n 0.965 0.965 0.965 rg 26.250 695.805 555.000 81.195 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 695.805 m 581.250 695.805 l 581.250 696.555 l 26.250 696.555 l f q 35.250 707.055 537.000 69.945 re W n 0.271 0.267 0.267 rg BT 35.250 766.011 Td /F4 9.8 Tf [(Fig. 3:)] TJ ET BT 35.250 744.775 Td /F4 9.8 Tf [(A.)] TJ ET BT 45.000 744.775 Td /F1 9.8 Tf [( Traces are averages of spontaneous EPSCs \(10-50 pA\) in MSSNs from running and non-running WT and R6/2 animals. )] TJ ET BT 35.250 731.038 Td /F1 9.8 Tf [(No significant differences in amplitude \(not shown\), decay time or half-amplitude duration were found. However, the rise )] TJ ET BT 35.250 717.302 Td /F1 9.8 Tf [(time was significantly shorter \(p=0.005\) in running compared to non-running WT mice.)] TJ ET Q BT 26.250 678.781 Td /F1 9.8 Tf [(BDNF protein content in non-running and running WT and R6/2 mice was determined biochemically using ELISA. At the ages )] TJ ET BT 26.250 666.876 Td /F1 9.8 Tf [(examined \(average 60 days\), no statistically significant differences in BDNF content were found among groups. There was a )] TJ ET BT 26.250 654.972 Td /F1 9.8 Tf [(small trend for higher BDNF in WT \(9.991.2 pg/g\) compared to R6/2 \(8.311.4 pg/g\) non-running mice and in WT \(9.941.5 )] TJ ET BT 26.250 643.067 Td /F1 9.8 Tf [(pg/g\) versus R6/2 \(8.690.4 pg/g\) running mice but the differences were not large enough to reach statistical significance. )] TJ ET BT 26.250 631.162 Td /F1 9.8 Tf [(Exercise did not change BDNF levels in WT or R6/2 mice indicating that running )] TJ ET BT 374.130 631.162 Td /F5 9.8 Tf [(per se)] TJ ET BT 401.225 631.162 Td /F1 9.8 Tf [( does not increase striatal BDNF content.)] TJ ET BT 26.250 611.757 Td /F4 9.8 Tf [(Adenosine:)] TJ ET BT 26.250 592.353 Td /F1 9.8 Tf [(The first adenosine receptor modulator we tested was KW 6002, a selective A)] TJ ET BT 361.689 590.288 Td /F1 8.7 Tf [(2A)] TJ ET BT 372.288 592.353 Td /F1 9.8 Tf [( receptor-antagonist. The effects of this )] TJ ET BT 26.250 580.448 Td /F1 9.8 Tf [(compound on spontaneous synaptic activity were inconsistent with cells displaying both increases and decreases in frequency )] TJ ET BT 26.250 568.543 Td /F1 9.8 Tf [(\(data not shown\), although proportionately more cells \(6/10\) from R6/2 mice showed increases in frequency compared to WT )] TJ ET BT 26.250 556.638 Td /F1 9.8 Tf [(cells \(2/9\). As A)] TJ ET BT 94.519 554.574 Td /F1 8.7 Tf [(2A)] TJ ET BT 105.119 556.638 Td /F1 9.8 Tf [( receptors are segregated in striatum, it was possible that the lack of consistency was due to recording from )] TJ ET BT 26.250 544.734 Td /F1 9.8 Tf [(different cell populations originating the direct \(non-A)] TJ ET BT 253.854 542.669 Td /F1 8.7 Tf [(2A)] TJ ET BT 264.453 544.734 Td /F1 9.8 Tf [( receptor-expressing\) or indirect \(A)] TJ ET BT 414.535 542.669 Td /F1 8.7 Tf [(2A)] TJ ET BT 425.134 544.734 Td /F1 9.8 Tf [( or D2 receptor-expressing\) )] TJ ET BT 26.250 532.829 Td /F1 9.8 Tf [(pathways. In consequence, we also used WT mice expressing EGFP in A)] TJ ET BT 343.798 530.765 Td /F1 8.7 Tf [(2A)] TJ ET BT 354.397 532.829 Td /F1 9.8 Tf [( adenosine or D2 dopamine receptor-containing )] TJ ET BT 26.250 520.924 Td /F1 9.8 Tf [(MSSNs. Again both increases and decreases were observed. However, more cells displayed decreases in frequency, in )] TJ ET BT 26.250 509.019 Td /F1 9.8 Tf [(agreement with the effects observed in unidentified WT MSSNs.)] TJ ET BT 26.250 489.615 Td /F1 9.8 Tf [(As previous evidence indicated that the same adenosine modulators could have differential effects on NMDA receptor-mediated )] TJ ET BT 26.250 477.710 Td /F1 9.8 Tf [(responses in WT and R6/2 mice )] TJ ET 0.267 0.267 0.267 rg BT 167.674 477.710 Td /F1 9.8 Tf [([26])] TJ ET 0.271 0.267 0.267 rg BT 183.937 477.710 Td /F1 9.8 Tf [( , we tested the effects of an A)] TJ ET BT 315.104 475.646 Td /F1 8.7 Tf [(2A)] TJ ET BT 325.703 477.710 Td /F1 9.8 Tf [( receptor agonist, CGS 21680. Indeed, this agonist )] TJ ET BT 26.250 465.805 Td /F1 9.8 Tf [(produced contrasting effects in MSSNs from WT and R6/2 mice. In WT mice the agonist produced small decreases in average )] TJ ET BT 26.250 453.900 Td /F1 9.8 Tf [(frequency of events whereas in cells from R6/2 mice it increased the frequency of spontaneous EPSCs \(Figure 4A, B\). )] TJ ET BT 26.250 441.996 Td /F1 9.8 Tf [(Cumulative inter-event histograms showed that CGS 21680 renormalized EPSC frequency in that there were fewer statistically )] TJ ET BT 26.250 430.091 Td /F1 9.8 Tf [(significant inter-event interval bin differences \(Figure 4C\).)] TJ ET 0.965 0.965 0.965 rg 26.250 54.570 555.000 365.640 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 420.210 m 581.250 420.210 l 581.250 419.460 l 26.250 419.460 l f q 221.250 0 0 225.000 35.250 185.460 cm /I6 Do Q q 35.250 54.570 537.000 124.890 re W n Q Q q 15.000 54.570 577.500 722.430 re W n 0.965 0.965 0.965 rg 26.250 695.805 555.000 81.195 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 695.805 m 581.250 695.805 l 581.250 696.555 l 26.250 696.555 l f q 35.250 707.055 537.000 69.945 re W n 0.271 0.267 0.267 rg BT 35.250 766.011 Td /F4 9.8 Tf [(Fig. 3:)] TJ ET BT 35.250 744.775 Td /F4 9.8 Tf [(A.)] TJ ET BT 45.000 744.775 Td /F1 9.8 Tf [( Traces are averages of spontaneous EPSCs \(10-50 pA\) in MSSNs from running and non-running WT and R6/2 animals. )] TJ ET BT 35.250 731.038 Td /F1 9.8 Tf [(No significant differences in amplitude \(not shown\), decay time or half-amplitude duration were found. However, the rise )] TJ ET BT 35.250 717.302 Td /F1 9.8 Tf [(time was significantly shorter \(p=0.005\) in running compared to non-running WT mice.)] TJ ET Q BT 26.250 678.781 Td /F1 9.8 Tf [(BDNF protein content in non-running and running WT and R6/2 mice was determined biochemically using ELISA. At the ages )] TJ ET BT 26.250 666.876 Td /F1 9.8 Tf [(examined \(average 60 days\), no statistically significant differences in BDNF content were found among groups. There was a )] TJ ET BT 26.250 654.972 Td /F1 9.8 Tf [(small trend for higher BDNF in WT \(9.991.2 pg/g\) compared to R6/2 \(8.311.4 pg/g\) non-running mice and in WT \(9.941.5 )] TJ ET BT 26.250 643.067 Td /F1 9.8 Tf [(pg/g\) versus R6/2 \(8.690.4 pg/g\) running mice but the differences were not large enough to reach statistical significance. )] TJ ET BT 26.250 631.162 Td /F1 9.8 Tf [(Exercise did not change BDNF levels in WT or R6/2 mice indicating that running )] TJ ET BT 374.130 631.162 Td /F5 9.8 Tf [(per se)] TJ ET BT 401.225 631.162 Td /F1 9.8 Tf [( does not increase striatal BDNF content.)] TJ ET BT 26.250 611.757 Td /F4 9.8 Tf [(Adenosine:)] TJ ET BT 26.250 592.353 Td /F1 9.8 Tf [(The first adenosine receptor modulator we tested was KW 6002, a selective A)] TJ ET BT 361.689 590.288 Td /F1 8.7 Tf [(2A)] TJ ET BT 372.288 592.353 Td /F1 9.8 Tf [( receptor-antagonist. The effects of this )] TJ ET BT 26.250 580.448 Td /F1 9.8 Tf [(compound on spontaneous synaptic activity were inconsistent with cells displaying both increases and decreases in frequency )] TJ ET BT 26.250 568.543 Td /F1 9.8 Tf [(\(data not shown\), although proportionately more cells \(6/10\) from R6/2 mice showed increases in frequency compared to WT )] TJ ET BT 26.250 556.638 Td /F1 9.8 Tf [(cells \(2/9\). As A)] TJ ET BT 94.519 554.574 Td /F1 8.7 Tf [(2A)] TJ ET BT 105.119 556.638 Td /F1 9.8 Tf [( receptors are segregated in striatum, it was possible that the lack of consistency was due to recording from )] TJ ET BT 26.250 544.734 Td /F1 9.8 Tf [(different cell populations originating the direct \(non-A)] TJ ET BT 253.854 542.669 Td /F1 8.7 Tf [(2A)] TJ ET BT 264.453 544.734 Td /F1 9.8 Tf [( receptor-expressing\) or indirect \(A)] TJ ET BT 414.535 542.669 Td /F1 8.7 Tf [(2A)] TJ ET BT 425.134 544.734 Td /F1 9.8 Tf [( or D2 receptor-expressing\) )] TJ ET BT 26.250 532.829 Td /F1 9.8 Tf [(pathways. In consequence, we also used WT mice expressing EGFP in A)] TJ ET BT 343.798 530.765 Td /F1 8.7 Tf [(2A)] TJ ET BT 354.397 532.829 Td /F1 9.8 Tf [( adenosine or D2 dopamine receptor-containing )] TJ ET BT 26.250 520.924 Td /F1 9.8 Tf [(MSSNs. Again both increases and decreases were observed. However, more cells displayed decreases in frequency, in )] TJ ET BT 26.250 509.019 Td /F1 9.8 Tf [(agreement with the effects observed in unidentified WT MSSNs.)] TJ ET BT 26.250 489.615 Td /F1 9.8 Tf [(As previous evidence indicated that the same adenosine modulators could have differential effects on NMDA receptor-mediated )] TJ ET BT 26.250 477.710 Td /F1 9.8 Tf [(responses in WT and R6/2 mice )] TJ ET 0.267 0.267 0.267 rg BT 167.674 477.710 Td /F1 9.8 Tf [([26])] TJ ET 0.271 0.267 0.267 rg BT 183.937 477.710 Td /F1 9.8 Tf [( , we tested the effects of an A)] TJ ET BT 315.104 475.646 Td /F1 8.7 Tf [(2A)] TJ ET BT 325.703 477.710 Td /F1 9.8 Tf [( receptor agonist, CGS 21680. Indeed, this agonist )] TJ ET BT 26.250 465.805 Td /F1 9.8 Tf [(produced contrasting effects in MSSNs from WT and R6/2 mice. In WT mice the agonist produced small decreases in average )] TJ ET BT 26.250 453.900 Td /F1 9.8 Tf [(frequency of events whereas in cells from R6/2 mice it increased the frequency of spontaneous EPSCs \(Figure 4A, B\). )] TJ ET BT 26.250 441.996 Td /F1 9.8 Tf [(Cumulative inter-event histograms showed that CGS 21680 renormalized EPSC frequency in that there were fewer statistically )] TJ ET BT 26.250 430.091 Td /F1 9.8 Tf [(significant inter-event interval bin differences \(Figure 4C\).)] TJ ET 0.965 0.965 0.965 rg 26.250 54.570 555.000 365.640 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 420.210 m 581.250 420.210 l 581.250 419.460 l 26.250 419.460 l f q 221.250 0 0 225.000 35.250 185.460 cm /I6 Do Q q 35.250 54.570 537.000 124.890 re W n Q Q q 221.250 0 0 225.000 35.250 185.460 cm /I6 Do Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(6)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 388 0 obj << /Type /Annot /Subtype /Link /A 389 0 R /Border [0 0 0] /H /I /Rect [ 167.6738 476.8081 183.9368 486.7287 ] >> endobj 389 0 obj << /Type /Action >> endobj 390 0 obj << /Type /Annot /Subtype /Link /A 391 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 185.4600 256.5000 410.4600 ] >> endobj 391 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2010/09/fig04.tif) >> endobj 392 0 obj << /Type /XObject /Subtype /Image /Width 295 /Height 300 /ColorSpace /DeviceRGB /Filter /DCTDecode /BitsPerComponent 8 /Length 25461>> stream JFIF;CREATOR: gd-jpeg v1.0 (using IJG JPEG v62), quality = 90 C     C   ,'" }!1AQa"q2#BR$3br %&'()*456789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz w!1AQaq"2B #3Rbr $4%&'()*56789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz ?aټ;˯ 7 շ7D5%99'|b+_{LYG%͕L0H~rnv4>0~n}+!xSnnl# 36+wyi}0H30B@A gWHOmX 2~9~Dk 䂑i0@9=' >lDAc~n|PiՍܐ%6M# ̐DB]l($VǃkLmCGk,čuc=S%E,d2_2x$Ԏqsv]eO*0.I85x 9xSZjZ},fd9 G< }̓K|.XIK~m*ZrR\da~%)$F;i$H1^h,0kn. x;Lf1rw2q׊׃ `v?W71gkVܾI\#c೿fI/[p79`Myt>}K+^M36=QG<;pFy1ch *k+J5ou+VOP{Y-l5-RVfBCFGgsi_Ķ ICew1 ;e?~2x`^~an 6Fr2*YyhDċTӥշ$mԢ+dE~A|EeRt'k'|9n9M^iֳ$HXߐyUɹ Y -λ+gh*1oO]gSEQk}aq$7{sx[k/ ;jV&lJk_^<[}}gM;\٪ZKQDWC"Z)ez3qq~,&C6Q4o Iͼċ0Ev> 𞱯^_j^(nu;zE ED>@b r):ཧ>P%q3ګmwO!YA1l.N}$~,\$k8݉!_7/˜ة?ിcV/ xU2m.mm*6=x<0kW{dl~@F Z;.<*auX(Ncm Ms&,p0@d30x{g⮛w9 i4IyfMda";[LbpFKrNkYZ^ i 4Rk٦+ ,k*W 2TAp(O٧KŞ z;Oh+xmx & '9"5j_Vw}#ZTF>\_`[CkH"HPHV5 3crĒ{MI@|iom}+=BT욶ڌ 3I;G+Xd ʗr0I;w֋֣P=ex^zXwlŽ7cE[ !F2Ƣy4uy@`*q|?'럊6r^욘ht;{MѦ\gkE#W^ мge[zmQonmȊ_Ep`&/!I5{JD̦=߽@[c>fIbK> +M 84+5hQOTE0 w(V0nHoO=&~MH.+Iddլ_(Ip#8).)M:LcC2+"WU$%W#zP?zG->0ɷX[pگ\!z yKGOOše;C +@CH 6ѓpWkN8#7RSa1  H5 In"YFHd2<+ßO37ڬ .n#,O|f8:,n,x]pN~~c&3@4kCx_]|;e[3H!uwdgs9vtc>4[;ݼ?dL^ #u8' 5|5w:_o_Yح߇F3g'gٯ4?|:AsY4ț2JБ'+#ag8=kKgo|7 ;xEaJAbY$5QZAam)Ԋ5 =(\GP hӿY#Yⷉ/-n nx#B=imm "0Q2Orp)s@ 4[İAfo$ƦK3@ f0 M'gӭ6 eT"t}*-J˘-bXPrT2}x4k(:lW2Z_qq_2y] 2I$ȬbXyY<`6 ؂:AH v4,r_Xk-Y"2dLC#C!@9 xƚ-l#2%X81S!!n3 jj|?Ku ɨD<&#rB/tOǬq< ŭɒ_9Kn8f!z(Q@"е;ol,/Hrw("na!VuR)kF ۳h͢3Iiǖ3m nĠ\h 4Eޡ{ks}kY̳.%rX@g|ouΥmr5 y5bHi!cxWh~*,֚7[{D[ȑ\IN\ f?Α[_ڮ&mq4akux 竑,O$"8,$6#Ldwʊ+684Sp]BcyDs=9B a*Pnjs I^RKs$$FgmdmI6|;J𮳦/jĶex>(6rO8miԙF\њMmFuݴm"1$(]*,YԱ$䚓m.EF\њMR@~2h|@|Am}J+H&a%|.TP?Qkuهux!Yҡ7IMo{|]"i)_|77/-XU{Ni%i'U1Ic#gPP?jZxGZ]L8b؏bRd 5s3ֵM6㯈F=#'6#p+'i'|mO.`n[h {9G[Zﭭ,PYqyZX98lr~ր> `ڗ5x>jѽuĎV//60@Jo4 )݌McF>Sh+ĺm;PƱwG#$% +8Wn[k:mޟyiu 4dJdҝ{1oI6G̬OA(&_s+IZokÅ-uɊCpyW=U~5uz'%v8m.GFC_>o4l Pe$̍r҃iזI\ϧ$!q<0sQǮ1ADQmw q{DLفr9/#IOKǻi2V"w2e 7?>+x.~$^t:t"/RXmV#"QюiTmmQ~T:z#G-$'y,+?li;Azn \܋IYvkǺzxwL-Kb_#Vɖ&4{ o@9' >%ZG?/1JurK8l- Co ,qƼP0 Ӿտ |">!j_|3au; ZFi"i-d;w$#8d8?m]xÿ-t,nfn $DV*c2,~,i x;VHB(Z luHcK=5U#Po}M~Yk߈|k1}ɾ6h @l({ZK*wyn0V?ҵ5MivŪd.^F;g@Ƀ_FcǗ6=gEhۓGګo J/mbKX4~k_kf}_"_HDAS|X"xWr$0/:Z%?=m o#/="ȡ@}MOiK"ap҃,-V?e墿5o]\;rŁ|WKVmX݄)ktY³$/9|QkVH4O^*/X,V]㷑'f 2~])xWX [B>|oѿkfB>?SPͳ~|'U5 -D>#7-p +rֻ?|J[Kc$iw$Ydp\C,JIZ^vQ }6H"n{-;c pLaqЭ?ys۝r21Ś:7lP6 jj^厏jm6//d3ىeskߠR_qXp7\4Y?-9&hzm2Z/y0Ϸ/ w _H k >Qlg~J͹֥ Q ֲ2x{ [;q3Gе, Vc(] zd]gdZRo~!w-rr1'Sڟz_كJ-Ԑ2Zmgrw[}7+|F_Ax/F<&#$7՘ƀ<^n=W`{Y|Q]A; >n8xj_tE{k4OKQ!Xv4EO=A Zig&0ywcv[=hMꑮ2Y4wǙ )md(<0:'?{/5㚉//gĭW~mtKDx|TFc;Ag]Dw4OMfJ->jr|'5rM4I f&QXz,_Rk_<n& &Uv>{GfqGQ0( 2( 3FE 0("(@z2( 3G`PkxgZdKf'A,J0( hn3d* '5E$$hHAvU' 0(8fm'M ͧ[ɮU{]:xcw vE@O~c [+g%Vh21iUiZe1-HUrB?ZΊ5&2^n $/$Z`P!Tx·z. 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B,%8_ÿ!DPjV8EmNb ƐH"3Nk}Ƈ#Xo*A,BE?H(e 0Z/ෆck:2qc̰6nP^{O3$$w|4^7VEdVp%v*`йx'YI$I$fc#^3bO@ :\z~lbI^WgwgvgrY$IZLџj;Ph(? endstream endobj 393 0 obj << /Type /Annot /Subtype /Link /A 394 0 R /Border [0 0 0] /H /I /Rect [ 167.6738 476.8081 183.9368 486.7287 ] >> endobj 394 0 obj << /Type /Action >> endobj 395 0 obj << /Type /Annot /Subtype /Link /A 396 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 185.4600 256.5000 410.4600 ] >> endobj 396 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2010/09/fig04.tif) >> endobj 397 0 obj << /Type /Annot /Subtype /Link /A 398 0 R /Border [0 0 0] /H /I /Rect [ 167.6738 476.8081 183.9368 486.7287 ] >> endobj 398 0 obj << /Type /Action >> endobj 399 0 obj << /Type /Annot /Subtype /Link /A 400 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 185.4600 256.5000 410.4600 ] >> endobj 400 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2010/09/fig04.tif) >> endobj 401 0 obj << /Type /Page /Parent 3 0 R /Annots [ 403 0 R 405 0 R 408 0 R 410 0 R 412 0 R 414 0 R ] /Contents 402 0 R >> endobj 402 0 obj << /Length 12597 >> stream q 15.000 51.081 577.500 725.919 re W n 0.965 0.965 0.965 rg 26.250 640.860 555.000 136.140 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 640.860 m 581.250 640.860 l 581.250 641.610 l 26.250 641.610 l f q 35.250 652.110 537.000 124.890 re W n 0.271 0.267 0.267 rg BT 35.250 766.011 Td /F4 9.8 Tf [(Fig. 4:)] TJ ET BT 35.250 744.775 Td /F4 9.8 Tf [(A.)] TJ ET BT 45.000 744.775 Td /F1 9.8 Tf [( CGS 21680, a selective A)] TJ ET BT 159.348 743.626 Td /F1 8.7 Tf [(2A)] TJ ET BT 169.947 744.775 Td /F1 9.8 Tf [(receptor agonist, produced differential effects on spontaneous EPSC frequency in WT and )] TJ ET BT 35.250 731.038 Td /F1 9.8 Tf [(R6/2 mice \(>60 days old\). Traces show that whereas in MSSNs from WT mice the agonist produced small decreases in )] TJ ET BT 35.250 717.302 Td /F1 9.8 Tf [(spontaneous synaptic events, in cells from R6/2 mice it increased the EPSC frequency. )] TJ ET BT 414.038 717.302 Td /F4 9.8 Tf [(B.)] TJ ET BT 423.788 717.302 Td /F1 9.8 Tf [( Graphs indicate significantly )] TJ ET BT 35.250 703.566 Td /F1 9.8 Tf [(reduced average EPSC frequency in cells from R6/2 compared to WT mice. In cells from WT mice the agonist produced a )] TJ ET BT 35.250 689.830 Td /F1 9.8 Tf [(small reduction in EPSC frequency whereas in cells from R6/2 mice it increased EPSC frequency. )] TJ ET BT 459.521 689.830 Td /F4 9.8 Tf [(C.)] TJ ET BT 469.271 689.830 Td /F1 9.8 Tf [( The cumulative inter-)] TJ ET BT 35.250 676.093 Td /F1 9.8 Tf [(event histograms show that CGS 21680 renormalizes EPSC frequency in that there were fewer statistically significant inter-)] TJ ET BT 35.250 662.357 Td /F1 9.8 Tf [(event bin differences between WT and R6/2 mice.)] TJ ET Q BT 26.250 623.836 Td /F4 9.8 Tf [(Ampakines:)] TJ ET BT 26.250 604.431 Td /F1 9.8 Tf [(At 5-7 and 11-12 weeks, MSSNs from R6/2 mice displayed significantly reduced average frequencies of spontaneous EPSCs )] TJ ET BT 26.250 592.527 Td /F1 9.8 Tf [(and mEPSCs compared to cells from WT animals )] TJ ET 0.267 0.267 0.267 rg BT 242.973 592.527 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 253.815 592.527 Td /F1 9.8 Tf [( . mEPSC frequencies for WT and R6/2 cells were 3.50.4 and 2.10.3 Hz )] TJ ET BT 26.250 580.622 Td /F1 9.8 Tf [(at 5-7 weeks and 2.60.3 and 1.30.2 Hz at 11-12 weeks, respectively. Cx614 increased the frequency and amplitude of )] TJ ET BT 26.250 568.717 Td /F1 9.8 Tf [(spontaneous and mEPSCs in a dose-dependent manner \(Figure 5A\). This effect occurred in WT and R6/2 mice at both ages. )] TJ ET BT 26.250 556.812 Td /F1 9.8 Tf [(The change in frequency in spontaneous and mEPSCs induced by a series of increasing concentrations of the ampakine is )] TJ ET BT 26.250 544.908 Td /F1 9.8 Tf [(shown in Figure 5B. At 5-7 weeks there was a monotonic increase in frequency in both WT and R6/2 cells whereas at 11-12 )] TJ ET BT 26.250 533.003 Td /F1 9.8 Tf [(weeks the increase in R6/2 cells was minor and reached a plateau at 100 M concentration with no further increases at the )] TJ ET BT 26.250 521.098 Td /F1 9.8 Tf [(higher concentration.)] TJ ET BT 26.250 501.693 Td /F1 9.8 Tf [(Examination of amplitude-frequency histograms indicated that, in spite of the increases in frequency of events, the difference )] TJ ET BT 26.250 489.789 Td /F1 9.8 Tf [(between MSSNs from WT and R6/2 still remained \(Figure 5C\). Inter-event interval probability distributions showed that addition )] TJ ET BT 26.250 477.884 Td /F1 9.8 Tf [(of Cx614 shifted the distributions to the left, indicating increased release probability \(Figure 5D\). However, while this shift was )] TJ ET BT 26.250 465.979 Td /F1 9.8 Tf [(very pronounced in cells from WT and R6/2 mice at 40 days, in cells from 80 day R6/2 mice the differences between the )] TJ ET BT 26.250 454.074 Td /F1 9.8 Tf [(distributions of events was not as pronounced.)] TJ ET 0.965 0.965 0.965 rg 26.250 51.081 555.000 393.113 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 444.193 m 581.250 444.193 l 581.250 443.443 l 26.250 443.443 l f q 212.250 0 0 225.000 35.250 209.443 cm /I7 Do Q q 35.250 51.081 537.000 152.363 re W n Q Q q 15.000 51.081 577.500 725.919 re W n 0.965 0.965 0.965 rg 26.250 640.860 555.000 136.140 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 640.860 m 581.250 640.860 l 581.250 641.610 l 26.250 641.610 l f q 35.250 652.110 537.000 124.890 re W n 0.271 0.267 0.267 rg BT 35.250 766.011 Td /F4 9.8 Tf [(Fig. 4:)] TJ ET BT 35.250 744.775 Td /F4 9.8 Tf [(A.)] TJ ET BT 45.000 744.775 Td /F1 9.8 Tf [( CGS 21680, a selective A)] TJ ET BT 159.348 743.626 Td /F1 8.7 Tf [(2A)] TJ ET BT 169.947 744.775 Td /F1 9.8 Tf [(receptor agonist, produced differential effects on spontaneous EPSC frequency in WT and )] TJ ET BT 35.250 731.038 Td /F1 9.8 Tf [(R6/2 mice \(>60 days old\). Traces show that whereas in MSSNs from WT mice the agonist produced small decreases in )] TJ ET BT 35.250 717.302 Td /F1 9.8 Tf [(spontaneous synaptic events, in cells from R6/2 mice it increased the EPSC frequency. )] TJ ET BT 414.038 717.302 Td /F4 9.8 Tf [(B.)] TJ ET BT 423.788 717.302 Td /F1 9.8 Tf [( Graphs indicate significantly )] TJ ET BT 35.250 703.566 Td /F1 9.8 Tf [(reduced average EPSC frequency in cells from R6/2 compared to WT mice. In cells from WT mice the agonist produced a )] TJ ET BT 35.250 689.830 Td /F1 9.8 Tf [(small reduction in EPSC frequency whereas in cells from R6/2 mice it increased EPSC frequency. )] TJ ET BT 459.521 689.830 Td /F4 9.8 Tf [(C.)] TJ ET BT 469.271 689.830 Td /F1 9.8 Tf [( The cumulative inter-)] TJ ET BT 35.250 676.093 Td /F1 9.8 Tf [(event histograms show that CGS 21680 renormalizes EPSC frequency in that there were fewer statistically significant inter-)] TJ ET BT 35.250 662.357 Td /F1 9.8 Tf [(event bin differences between WT and R6/2 mice.)] TJ ET Q BT 26.250 623.836 Td /F4 9.8 Tf [(Ampakines:)] TJ ET BT 26.250 604.431 Td /F1 9.8 Tf [(At 5-7 and 11-12 weeks, MSSNs from R6/2 mice displayed significantly reduced average frequencies of spontaneous EPSCs )] TJ ET BT 26.250 592.527 Td /F1 9.8 Tf [(and mEPSCs compared to cells from WT animals )] TJ ET 0.267 0.267 0.267 rg BT 242.973 592.527 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 253.815 592.527 Td /F1 9.8 Tf [( . mEPSC frequencies for WT and R6/2 cells were 3.50.4 and 2.10.3 Hz )] TJ ET BT 26.250 580.622 Td /F1 9.8 Tf [(at 5-7 weeks and 2.60.3 and 1.30.2 Hz at 11-12 weeks, respectively. Cx614 increased the frequency and amplitude of )] TJ ET BT 26.250 568.717 Td /F1 9.8 Tf [(spontaneous and mEPSCs in a dose-dependent manner \(Figure 5A\). This effect occurred in WT and R6/2 mice at both ages. )] TJ ET BT 26.250 556.812 Td /F1 9.8 Tf [(The change in frequency in spontaneous and mEPSCs induced by a series of increasing concentrations of the ampakine is )] TJ ET BT 26.250 544.908 Td /F1 9.8 Tf [(shown in Figure 5B. At 5-7 weeks there was a monotonic increase in frequency in both WT and R6/2 cells whereas at 11-12 )] TJ ET BT 26.250 533.003 Td /F1 9.8 Tf [(weeks the increase in R6/2 cells was minor and reached a plateau at 100 M concentration with no further increases at the )] TJ ET BT 26.250 521.098 Td /F1 9.8 Tf [(higher concentration.)] TJ ET BT 26.250 501.693 Td /F1 9.8 Tf [(Examination of amplitude-frequency histograms indicated that, in spite of the increases in frequency of events, the difference )] TJ ET BT 26.250 489.789 Td /F1 9.8 Tf [(between MSSNs from WT and R6/2 still remained \(Figure 5C\). Inter-event interval probability distributions showed that addition )] TJ ET BT 26.250 477.884 Td /F1 9.8 Tf [(of Cx614 shifted the distributions to the left, indicating increased release probability \(Figure 5D\). However, while this shift was )] TJ ET BT 26.250 465.979 Td /F1 9.8 Tf [(very pronounced in cells from WT and R6/2 mice at 40 days, in cells from 80 day R6/2 mice the differences between the )] TJ ET BT 26.250 454.074 Td /F1 9.8 Tf [(distributions of events was not as pronounced.)] TJ ET 0.965 0.965 0.965 rg 26.250 51.081 555.000 393.113 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 444.193 m 581.250 444.193 l 581.250 443.443 l 26.250 443.443 l f q 212.250 0 0 225.000 35.250 209.443 cm /I7 Do Q q 35.250 51.081 537.000 152.363 re W n Q Q q 15.000 51.081 577.500 725.919 re W n 0.965 0.965 0.965 rg 26.250 640.860 555.000 136.140 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 640.860 m 581.250 640.860 l 581.250 641.610 l 26.250 641.610 l f q 35.250 652.110 537.000 124.890 re W n 0.271 0.267 0.267 rg BT 35.250 766.011 Td /F4 9.8 Tf [(Fig. 4:)] TJ ET BT 35.250 744.775 Td /F4 9.8 Tf [(A.)] TJ ET BT 45.000 744.775 Td /F1 9.8 Tf [( CGS 21680, a selective A)] TJ ET BT 159.348 743.626 Td /F1 8.7 Tf [(2A)] TJ ET BT 169.947 744.775 Td /F1 9.8 Tf [(receptor agonist, produced differential effects on spontaneous EPSC frequency in WT and )] TJ ET BT 35.250 731.038 Td /F1 9.8 Tf [(R6/2 mice \(>60 days old\). Traces show that whereas in MSSNs from WT mice the agonist produced small decreases in )] TJ ET BT 35.250 717.302 Td /F1 9.8 Tf [(spontaneous synaptic events, in cells from R6/2 mice it increased the EPSC frequency. )] TJ ET BT 414.038 717.302 Td /F4 9.8 Tf [(B.)] TJ ET BT 423.788 717.302 Td /F1 9.8 Tf [( Graphs indicate significantly )] TJ ET BT 35.250 703.566 Td /F1 9.8 Tf [(reduced average EPSC frequency in cells from R6/2 compared to WT mice. In cells from WT mice the agonist produced a )] TJ ET BT 35.250 689.830 Td /F1 9.8 Tf [(small reduction in EPSC frequency whereas in cells from R6/2 mice it increased EPSC frequency. )] TJ ET BT 459.521 689.830 Td /F4 9.8 Tf [(C.)] TJ ET BT 469.271 689.830 Td /F1 9.8 Tf [( The cumulative inter-)] TJ ET BT 35.250 676.093 Td /F1 9.8 Tf [(event histograms show that CGS 21680 renormalizes EPSC frequency in that there were fewer statistically significant inter-)] TJ ET BT 35.250 662.357 Td /F1 9.8 Tf [(event bin differences between WT and R6/2 mice.)] TJ ET Q BT 26.250 623.836 Td /F4 9.8 Tf [(Ampakines:)] TJ ET BT 26.250 604.431 Td /F1 9.8 Tf [(At 5-7 and 11-12 weeks, MSSNs from R6/2 mice displayed significantly reduced average frequencies of spontaneous EPSCs )] TJ ET BT 26.250 592.527 Td /F1 9.8 Tf [(and mEPSCs compared to cells from WT animals )] TJ ET 0.267 0.267 0.267 rg BT 242.973 592.527 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 253.815 592.527 Td /F1 9.8 Tf [( . mEPSC frequencies for WT and R6/2 cells were 3.50.4 and 2.10.3 Hz )] TJ ET BT 26.250 580.622 Td /F1 9.8 Tf [(at 5-7 weeks and 2.60.3 and 1.30.2 Hz at 11-12 weeks, respectively. Cx614 increased the frequency and amplitude of )] TJ ET BT 26.250 568.717 Td /F1 9.8 Tf [(spontaneous and mEPSCs in a dose-dependent manner \(Figure 5A\). This effect occurred in WT and R6/2 mice at both ages. )] TJ ET BT 26.250 556.812 Td /F1 9.8 Tf [(The change in frequency in spontaneous and mEPSCs induced by a series of increasing concentrations of the ampakine is )] TJ ET BT 26.250 544.908 Td /F1 9.8 Tf [(shown in Figure 5B. At 5-7 weeks there was a monotonic increase in frequency in both WT and R6/2 cells whereas at 11-12 )] TJ ET BT 26.250 533.003 Td /F1 9.8 Tf [(weeks the increase in R6/2 cells was minor and reached a plateau at 100 M concentration with no further increases at the )] TJ ET BT 26.250 521.098 Td /F1 9.8 Tf [(higher concentration.)] TJ ET BT 26.250 501.693 Td /F1 9.8 Tf [(Examination of amplitude-frequency histograms indicated that, in spite of the increases in frequency of events, the difference )] TJ ET BT 26.250 489.789 Td /F1 9.8 Tf [(between MSSNs from WT and R6/2 still remained \(Figure 5C\). Inter-event interval probability distributions showed that addition )] TJ ET BT 26.250 477.884 Td /F1 9.8 Tf [(of Cx614 shifted the distributions to the left, indicating increased release probability \(Figure 5D\). However, while this shift was )] TJ ET BT 26.250 465.979 Td /F1 9.8 Tf [(very pronounced in cells from WT and R6/2 mice at 40 days, in cells from 80 day R6/2 mice the differences between the )] TJ ET BT 26.250 454.074 Td /F1 9.8 Tf [(distributions of events was not as pronounced.)] TJ ET 0.965 0.965 0.965 rg 26.250 51.081 555.000 393.113 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 444.193 m 581.250 444.193 l 581.250 443.443 l 26.250 443.443 l f q 212.250 0 0 225.000 35.250 209.443 cm /I7 Do Q q 35.250 51.081 537.000 152.363 re W n Q Q q 212.250 0 0 225.000 35.250 209.443 cm /I7 Do Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(7)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 403 0 obj << /Type /Annot /Subtype /Link /A 404 0 R /Border [0 0 0] /H /I /Rect [ 242.9730 591.6248 253.8150 601.5454 ] >> endobj 404 0 obj << /Type /Action >> endobj 405 0 obj << /Type /Annot /Subtype /Link /A 406 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 209.4435 247.5000 434.4435 ] >> endobj 406 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2010/09/fig05.tif) >> endobj 407 0 obj << /Type /XObject /Subtype /Image /Width 283 /Height 300 /ColorSpace /DeviceRGB /Filter /DCTDecode /BitsPerComponent 8 /Length 25578>> stream JFIF;CREATOR: gd-jpeg v1.0 (using IJG JPEG v62), quality = 90 C     C   ," }!1AQa"q2#BR$3br %&'()*456789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz w!1AQaq"2B #3Rbr $4%&'()*56789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz ?RRbw3𲆛ҍ#?jK>^7(]Ν|HasbkDt9nb}(8kj߶m|A~|;G}i8Rm#6+}E|~k$=xTo6 H8^kHul19Y-f2:ućA}X+M]m.>||dQ!z)f;ojŶ>1ts(32',q=@߆`SC+-oxy#4?/FFcQ;M=܋K4.b.vL^WrQլ4 _mhR7zmsAAp!$oo.o°m [8<rkIuEtwKgg2i!oH m+1Pvp-Az+]S/m>i_5ggc9gs@>5ž-'M-&f1!j++c˃ljE*C mGe9;nfc _/D|,eKaۀ#$,hx;> <sr|]h~c:%ycmr%6bi ȷUd r(#q0 ~'O Fe£M& pt&0|,@ubS_3YF#lcYNAF0A׼k4m# .v 5bE-l?#j}n[j!$UBpp89ۑ=vj6im:Y-tSp_rI-zrkh߷f &nG h IGN~Q_y]ZZ̞6_1g{lpA!>Ɲ][n/?Ӽ[itҴu iK/ߐB 3]"3D$G; ދdH oźͤGҴm*_[C&L!On18U<,]׿wԾiZ߇u)| l&t9bEb3'sn8ˬ<7^ }R)H1^"C1 v=)5/xl"Is=G- |Es8ki:5kú|ߴ OrRO<-9`vlUsWZuh׈m-@l l$' ,ߓ4IֱN.%H1b;pV2Ü /xƭmӢ-cy{nkY\xQ6d>m[|IĶ|=6xΗáG2@Wl!?x% ~?|XDƴFQe0$R g@B4_xG|-WO7:o\,Es Qp =A??0=+6 XR@R),)i~4~4~_PT̷2F`A Xhhɾ< Ҿ6i0Zi*,*'2qX[ l22~j_ƀ>{׾~+BI}3,K7S@}ߐx5gtqm?TC:m JpHOhk턐%ӭx`,j# 6VQޏ/[?]wTu-uHi a. )R@?h1Pi5ԱGds"QTP4x|=]L6vۣ!T.N;W)ֺN+)GlJj"PN$΀QQyoͧXjs2}FIdwUe݃ns@5/՝Rj+I&spUx!2>18k>=~k:fl-L$L'rM_G@~0yo $̸e,Wۃ$i?.rn::@  )0)# Lc/fOQ4ُ8Wv%KYIsŖ1# ߳?}Mg{JvZ豭-G@Eꡎ~U  nOoڂȲƷj,URYr`X`:e.t?hm K LyWwمn,c1fueU`Ts~jM'QTj+M&22ɶB,e@^1.]F _/H{%,ю d_qG@ 5~*\4*ܮ?4$•r#qm6Oq߲_:ol4 TYdo>׌e13QP?k{x4sWQ;XXɴ$k{ 6@%3^fWjv\#%:~Di"DTe s͸7<huy}.1[ zߵ߄ү`ij!iWX[M2ImܴxCb΋"u d}èKg$Omec@ A=~پP^o).A呚MС173t( ;tSyw= Fwyv24q0%60 nϓj?|!|<}>(eІ)u -"}$Ȅ#X8UѼmx[;jUTRFsF393'-紊Ky$;۹"YS~"|3a|]ܞlSʈl EL _~_ -Ͷ=nkXqN _TM*=YmVR@qYE|O|4oma4Lڍ,FѣC,>JDIbۋ6~o'OQ3&tkMoN=ƬM$&]=2/0H^MyAe1,1|djaTp('7M:n<i5(tH4H)%`'0qТikSHb0 #!`T(Pҗ4_Dm[FKy/GK@$$.sE$ü=~5>5[xdF# aI*\6'7¹- E'wpZXDOO< ߰[xKޥ=[.fUW[lU#gm< ]S!o._o5k{B<`Tv }W';E>?7ڀ>C?c5i:/M4cY$9Y'Fgj2y! 9>|zӮ<=i"#0qŘ2$ ݟÍR-[DiDQqcc, 8{IIKQPqGZ8v?W/ F7b}=BL(cCoRBJxZ)M'qK|UmM[Xewon" FB#Fzq\KFh4g8T#N? u}_؝V^ݧom&Lgr.rǭRu;_IBQ9eUU%Ij[xRIR7Dm '?Z8⹊y&HIU`J6oC h+Xӥ4I+qm描}/Zz@ ǭz.k[iwPʰI # b4/xkRuqrC{,e$78ZŗP_Ӷ}f% y8L1lG*MI2Aǭzb4E7*b;>]HC*I#`FAuwGfZ8kZ/յ{ -Wx!2*\2:dggĿ4O VcD]ƣ7N>GyN@zŅ]"/c>Oڎcv}FCX1Fy!8$}@\zFU:εhq,Gn3qӦGlfIZEܲ]Bg(C~R/]s8M{KӬt֓ZjK#PcV$~ߊ|1]KSY'O+bFd..gw8~= /5j_?jRQ `R%8$}o0Vj 63bH;HbA9~*w]kwzTr6s-;YFvUpx4-3!%@ȯ1g? y5V;ա)uE.LR4|V| ,_BFWn@><-ϊ+]cS𾟥]O KJ~T8A4b$֌қG]][NEnRr Ѷ8l@ Ū_'2[yRs0 ~@AXbF\۷x?K-m$IhYhƌث a'%+μ b 0~3Oh9_~i}ͼ 9'T]^H%br7(Xm'T8>«\B4&^9nX}A5Ꮚ.|16 CJsI7 !29]Ju+kϟq(CZǁE֡7c 3N?Yb>v|04u=xy=(Z}& n.eܶnfO-lf+*~ i> ֗qx "P) cjgl&ع|ǥzP_#=VQ sE ~XYnO8]*xp|MkE_,i1)'A\gzGnRw●JKeݝսƮ.mLF9$q*b ,$k5'9HGai POhX^7 Ó]0ZjXc+֕bmLH yp2@Tӵu{W IJIގF{\Vc4?03R#yׂm;+$s2Z"CJ [2zlך%`X, KnWGj?t]^;oL6~$ ȬlͣAiw=½+_C]_΍3G8U?9:c\G<_-w-ÌOQKH]Ge&՘xB1$kw}$7@U!t sǰ h2gi" ỈH*U=>U=/FgÙe1mʼnR2I'[LxziHvªO@C?ta9Fuy4k!}ṕ9]VIԜ۲E}mMoƼwN|Uдht?~,u6M)I»,b̋W9Gm?G? k:=62 I2~cl3A-cDX-q\Ap>d"Ȫw)IQ`ʿڿ3^jrz :+@nd,V`IMmQ@ZCg o pD,qU@++(P/ ~'5d[kxIW P,I=OS@WOLtr|Rq;<cnc(2bcexU7W}N}֧m3F46;{ZW`DV?X,4ˋ8//'ɵyUy6؀`K<-/CZ~q{I7Ŭ,Ab*>L7z=[XM}I1v  @t75(EeW llj!;Nd-#Ey~ _O_Msyk 6̈EiZvcF[F%mX>P%Rm ?pc1I> } wyc6WVSP5FX},ᑟ=yU oHڱkLMX69@>eaTBzu )hPQKG4QYxLw:wmm䶜H]Q0Y~)h))h()p}hǽ'GKz0}hiMEtJ5KxY.vߘnۖ=w6)Ghr1pOsX?JxofY&Gt$*]B:9B5][7ZmWoyey`{g2ۀ  ~#zxCw}m%oMy%E^5a~N bk+ |HYMgQү4*}2X Ei|$ٟd;؛ ׶xW1]MzVJE̿}T@8din\a)ޟ2otf kgTln^9eH*[Ǡ'e7u L>8o0,*ߊ c}O#^c2tV¦>su)SN\Z啚;;E}|+V?ƕu1WPa:W F JgحϽ>A_Oe=oqi+Ȏ!drggBis޷~o[kU \6b# zwS|U~cOJ5Ul%JQ֩=zI&on? N3\?\XԐ?,5I!vʇ_W1#d<-&{jnx& $f%nvK{h/ͬ 9A6]b\<sy_,m޹erɼGz4mi<`y<'xX ՕK  g [Vp[kwN@'Xjs~,_zަGtZ? xĺ/藾 Դw6֣3I(hf{<|+N*izu,kYT,ߙ?'KQj??Ҁ֗(h֗(h7M馌\ H1,dꅈ Hdu?<]gsn.Z@!#/?R㘠Iu]KJ"tLwޏ0zַ7a|ϲKwL8x//|Mׄ<)kcxĺ|7#[G>v ƱZGjY3gӜhG÷^"mbZj(Os]\Ч.g:oN?3b*QP\k+ݴ}oRg-ck?ADY%rW_ºJNMƓ()&=i ? 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A|6ɼnھ7`@hA [?ʍmO'iI-ixKֺj |v3ʐC,  } Er^VگȵGdAk22>= >e:T?dq·;ހ<{G|K¾/m6[4 - My:p!#r7cO῅u;E?촷r!'= ki{P9yN6~ӚpŜh9'`=xxkQF^ɏ͵u'o|6 * l}Er'۝M:LJtͼ/wvY‚`gkgotx[ү5-rKil#ۏ.W 3JExo> endobj 409 0 obj << /Type /Action >> endobj 410 0 obj << /Type /Annot /Subtype /Link /A 411 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 209.4435 247.5000 434.4435 ] >> endobj 411 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2010/09/fig05.tif) >> endobj 412 0 obj << /Type /Annot /Subtype /Link /A 413 0 R /Border [0 0 0] /H /I /Rect [ 242.9730 591.6248 253.8150 601.5454 ] >> endobj 413 0 obj << /Type /Action >> endobj 414 0 obj << /Type /Annot /Subtype /Link /A 415 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 209.4435 247.5000 434.4435 ] >> endobj 415 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2010/09/fig05.tif) >> endobj 416 0 obj << /Type /Page /Parent 3 0 R /Annots [ 418 0 R 420 0 R 422 0 R 425 0 R 427 0 R 429 0 R 431 0 R 433 0 R 435 0 R ] /Contents 417 0 R >> endobj 417 0 obj << /Length 17496 >> stream q 15.000 22.651 577.500 754.349 re W n 0.965 0.965 0.965 rg 26.250 613.387 555.000 163.613 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 613.387 m 581.250 613.387 l 581.250 614.137 l 26.250 614.137 l f q 35.250 624.637 537.000 152.363 re W n 0.271 0.267 0.267 rg BT 35.250 766.011 Td /F4 9.8 Tf [(Fig. 5:)] TJ ET BT 35.250 744.775 Td /F4 9.8 Tf [(A.)] TJ ET BT 45.000 744.775 Td /F1 9.8 Tf [( Traces are examples of spontaneous mEPSCs [in the presence of TTX \(1 M\)] recorded in WT and R6/2 mice \(11-12 )] TJ ET BT 35.250 731.038 Td /F1 9.8 Tf [(weeks of age\) in the absence \(left\) or presence of a low \(20 mM, middle\) and a high concentration \(100 mM, right\) of )] TJ ET BT 35.250 717.302 Td /F1 9.8 Tf [(Cx614. )] TJ ET BT 68.849 717.302 Td /F4 9.8 Tf [(B.)] TJ ET BT 78.599 717.302 Td /F1 9.8 Tf [( Graphs show concentration-response relationships of average frequencies of spontaneous and mEPSCs )] TJ ET BT 35.250 703.566 Td /F1 9.8 Tf [(between WT and R6/2 mice at 5-7 and 11-12 weeks. Note that the increase in frequency produced at 5-7 weeks by Cx614 )] TJ ET BT 35.250 689.830 Td /F1 9.8 Tf [(is less prominent in cells from both WT and R6/2 mice at 11-12 weeks of age. )] TJ ET BT 372.298 689.830 Td /F4 9.8 Tf [(C.)] TJ ET BT 382.048 689.830 Td /F1 9.8 Tf [( and )] TJ ET BT 403.732 689.830 Td /F4 9.8 Tf [(D.)] TJ ET BT 413.482 689.830 Td /F1 9.8 Tf [( Graphs show amplitude-frequency )] TJ ET BT 35.250 676.093 Td /F1 9.8 Tf [(histograms \( )] TJ ET BT 91.595 676.093 Td /F4 9.8 Tf [(C)] TJ ET BT 98.635 676.093 Td /F1 9.8 Tf [( \) and cumulative probability distributions of inter-event intervals \( )] TJ ET BT 382.028 676.093 Td /F4 9.8 Tf [(D)] TJ ET BT 389.068 676.093 Td /F1 9.8 Tf [( \) of mEPSCs in MSSNs from WT and )] TJ ET BT 35.250 662.357 Td /F1 9.8 Tf [(R6/2 mice before and after Cx614 \(at 11-12 weeks of age\). In spite of an increase in frequency of mEPSCs after Cx614, the )] TJ ET BT 35.250 648.621 Td /F1 9.8 Tf [(difference between WT and R6/2 cells still remains. Line and asterisk indicate statistically significant differences between )] TJ ET BT 35.250 634.885 Td /F1 9.8 Tf [(values for WT and R6/2 mice \(p<0.05-0.001\).)] TJ ET Q BT 26.250 596.364 Td /F1 9.8 Tf [(Cx614 also affected the amplitude and kinetics of spontaneous and mEPSCs. Amplitudes, rise and decay times, as well as half-)] TJ ET BT 26.250 584.459 Td /F1 9.8 Tf [(amplitude durations increased after drug application \(Figure 6A\). These changes in frequency and amplitude/kinetics indicate )] TJ ET BT 26.250 572.554 Td /F1 9.8 Tf [(that Cx614 could have both pre- and post-synaptic effects. In addition to the observed effects on frequency of spontaneous and )] TJ ET BT 26.250 560.649 Td /F1 9.8 Tf [(mEPSCs, in a population of MSSNs from R6/2 mice Cx614, even at low concentrations, induced periodic inward currents )] TJ ET BT 26.250 548.745 Td /F1 9.8 Tf [(accompanied by bursts of high-frequency synaptic activity \(Figure 6B\). These episodes could reflect propagation of burst firing )] TJ ET BT 26.250 536.840 Td /F1 9.8 Tf [(from cortical pyramidal neurons )] TJ ET 0.267 0.267 0.267 rg BT 164.953 536.840 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 175.796 536.840 Td /F1 9.8 Tf [( , as well as increased excitability in cortical neurons in R6/2 mice )] TJ ET 0.267 0.267 0.267 rg BT 460.808 536.840 Td /F1 9.8 Tf [([11])] TJ ET 0.271 0.267 0.267 rg BT 477.070 536.840 Td /F1 9.8 Tf [( .)] TJ ET 0.965 0.965 0.965 rg 26.250 177.541 555.000 349.418 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 526.959 m 581.250 526.959 l 581.250 526.209 l 26.250 526.209 l f 26.250 177.541 m 581.250 177.541 l 581.250 178.291 l 26.250 178.291 l f q 199.500 0 0 225.000 35.250 292.209 cm /I8 Do Q q 35.250 188.791 537.000 97.418 re W n 0.271 0.267 0.267 rg BT 35.250 275.220 Td /F4 9.8 Tf [(Fig. 6:)] TJ ET BT 35.250 253.984 Td /F4 9.8 Tf [(A.)] TJ ET BT 45.000 253.984 Td /F1 9.8 Tf [( Traces are average spontaneous and mEPSCs in TTX and after bath application of increasing concentrations of Cx614. )] TJ ET BT 35.250 240.247 Td /F1 9.8 Tf [(The ampakine increased the amplitude and reduced deactivation of AMPA receptors as indicated by increases in decay )] TJ ET BT 35.250 226.511 Td /F1 9.8 Tf [(time and half-amplitude duration. )] TJ ET BT 179.940 226.511 Td /F4 9.8 Tf [(B.)] TJ ET BT 189.690 226.511 Td /F1 9.8 Tf [( Arrows show large, periodic inward currents were evoked by Cx614 in R6/2 but not WT )] TJ ET BT 35.250 212.775 Td /F1 9.8 Tf [(mice. Representative traces recorded in the presence of Cx614 \(100 mM\) in MSSNs from WT and R6/2 mice at 6-7 and 11-)] TJ ET BT 35.250 199.039 Td /F1 9.8 Tf [(12 weeks.)] TJ ET Q BT 26.250 143.320 Td /F4 12.0 Tf [(Discussion)] TJ ET BT 26.250 123.366 Td /F1 9.8 Tf [(A number of behavioral and pharmacological manipulations known to delay the progression of neurodegenerative disorders )] TJ ET BT 26.250 111.461 Td /F1 9.8 Tf [(were tested, with the goal of rescuing the deficits in glutamatergic synaptic activity along the corticostriatal pathway in the R6/2 )] TJ ET BT 26.250 99.556 Td /F1 9.8 Tf [(mouse model of HD. Each of these manipulations produced some of the desired effects, but only in a partial manner and in )] TJ ET BT 26.250 87.651 Td /F1 9.8 Tf [(some cases with the potential of inducing adverse reactions.)] TJ ET BT 26.250 68.247 Td /F4 9.8 Tf [(Exercise:)] TJ ET BT 26.250 48.842 Td /F1 9.8 Tf [(Physical activity has shown promising effects in a number of neurodegenerative disorders including PD, AD, as well as other )] TJ ET BT 26.250 36.937 Td /F1 9.8 Tf [(pathologies. When associated with an enriched environment, exercise can delay progression of the phenotype and reduce the )] TJ ET Q q 15.000 22.651 577.500 754.349 re W n 0.965 0.965 0.965 rg 26.250 613.387 555.000 163.613 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 613.387 m 581.250 613.387 l 581.250 614.137 l 26.250 614.137 l f q 35.250 624.637 537.000 152.363 re W n 0.271 0.267 0.267 rg BT 35.250 766.011 Td /F4 9.8 Tf [(Fig. 5:)] TJ ET BT 35.250 744.775 Td /F4 9.8 Tf [(A.)] TJ ET BT 45.000 744.775 Td /F1 9.8 Tf [( Traces are examples of spontaneous mEPSCs [in the presence of TTX \(1 M\)] recorded in WT and R6/2 mice \(11-12 )] TJ ET BT 35.250 731.038 Td /F1 9.8 Tf [(weeks of age\) in the absence \(left\) or presence of a low \(20 mM, middle\) and a high concentration \(100 mM, right\) of )] TJ ET BT 35.250 717.302 Td /F1 9.8 Tf [(Cx614. )] TJ ET BT 68.849 717.302 Td /F4 9.8 Tf [(B.)] TJ ET BT 78.599 717.302 Td /F1 9.8 Tf [( Graphs show concentration-response relationships of average frequencies of spontaneous and mEPSCs )] TJ ET BT 35.250 703.566 Td /F1 9.8 Tf [(between WT and R6/2 mice at 5-7 and 11-12 weeks. Note that the increase in frequency produced at 5-7 weeks by Cx614 )] TJ ET BT 35.250 689.830 Td /F1 9.8 Tf [(is less prominent in cells from both WT and R6/2 mice at 11-12 weeks of age. )] TJ ET BT 372.298 689.830 Td /F4 9.8 Tf [(C.)] TJ ET BT 382.048 689.830 Td /F1 9.8 Tf [( and )] TJ ET BT 403.732 689.830 Td /F4 9.8 Tf [(D.)] TJ ET BT 413.482 689.830 Td /F1 9.8 Tf [( Graphs show amplitude-frequency )] TJ ET BT 35.250 676.093 Td /F1 9.8 Tf [(histograms \( )] TJ ET BT 91.595 676.093 Td /F4 9.8 Tf [(C)] TJ ET BT 98.635 676.093 Td /F1 9.8 Tf [( \) and cumulative probability distributions of inter-event intervals \( )] TJ ET BT 382.028 676.093 Td /F4 9.8 Tf [(D)] TJ ET BT 389.068 676.093 Td /F1 9.8 Tf [( \) of mEPSCs in MSSNs from WT and )] TJ ET BT 35.250 662.357 Td /F1 9.8 Tf [(R6/2 mice before and after Cx614 \(at 11-12 weeks of age\). In spite of an increase in frequency of mEPSCs after Cx614, the )] TJ ET BT 35.250 648.621 Td /F1 9.8 Tf [(difference between WT and R6/2 cells still remains. Line and asterisk indicate statistically significant differences between )] TJ ET BT 35.250 634.885 Td /F1 9.8 Tf [(values for WT and R6/2 mice \(p<0.05-0.001\).)] TJ ET Q BT 26.250 596.364 Td /F1 9.8 Tf [(Cx614 also affected the amplitude and kinetics of spontaneous and mEPSCs. Amplitudes, rise and decay times, as well as half-)] TJ ET BT 26.250 584.459 Td /F1 9.8 Tf [(amplitude durations increased after drug application \(Figure 6A\). These changes in frequency and amplitude/kinetics indicate )] TJ ET BT 26.250 572.554 Td /F1 9.8 Tf [(that Cx614 could have both pre- and post-synaptic effects. In addition to the observed effects on frequency of spontaneous and )] TJ ET BT 26.250 560.649 Td /F1 9.8 Tf [(mEPSCs, in a population of MSSNs from R6/2 mice Cx614, even at low concentrations, induced periodic inward currents )] TJ ET BT 26.250 548.745 Td /F1 9.8 Tf [(accompanied by bursts of high-frequency synaptic activity \(Figure 6B\). These episodes could reflect propagation of burst firing )] TJ ET BT 26.250 536.840 Td /F1 9.8 Tf [(from cortical pyramidal neurons )] TJ ET 0.267 0.267 0.267 rg BT 164.953 536.840 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 175.796 536.840 Td /F1 9.8 Tf [( , as well as increased excitability in cortical neurons in R6/2 mice )] TJ ET 0.267 0.267 0.267 rg BT 460.808 536.840 Td /F1 9.8 Tf [([11])] TJ ET 0.271 0.267 0.267 rg BT 477.070 536.840 Td /F1 9.8 Tf [( .)] TJ ET 0.965 0.965 0.965 rg 26.250 177.541 555.000 349.418 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 526.959 m 581.250 526.959 l 581.250 526.209 l 26.250 526.209 l f 26.250 177.541 m 581.250 177.541 l 581.250 178.291 l 26.250 178.291 l f q 199.500 0 0 225.000 35.250 292.209 cm /I8 Do Q q 35.250 188.791 537.000 97.418 re W n 0.271 0.267 0.267 rg BT 35.250 275.220 Td /F4 9.8 Tf [(Fig. 6:)] TJ ET BT 35.250 253.984 Td /F4 9.8 Tf [(A.)] TJ ET BT 45.000 253.984 Td /F1 9.8 Tf [( Traces are average spontaneous and mEPSCs in TTX and after bath application of increasing concentrations of Cx614. )] TJ ET BT 35.250 240.247 Td /F1 9.8 Tf [(The ampakine increased the amplitude and reduced deactivation of AMPA receptors as indicated by increases in decay )] TJ ET BT 35.250 226.511 Td /F1 9.8 Tf [(time and half-amplitude duration. )] TJ ET BT 179.940 226.511 Td /F4 9.8 Tf [(B.)] TJ ET BT 189.690 226.511 Td /F1 9.8 Tf [( Arrows show large, periodic inward currents were evoked by Cx614 in R6/2 but not WT )] TJ ET BT 35.250 212.775 Td /F1 9.8 Tf [(mice. Representative traces recorded in the presence of Cx614 \(100 mM\) in MSSNs from WT and R6/2 mice at 6-7 and 11-)] TJ ET BT 35.250 199.039 Td /F1 9.8 Tf [(12 weeks.)] TJ ET Q BT 26.250 143.320 Td /F4 12.0 Tf [(Discussion)] TJ ET BT 26.250 123.366 Td /F1 9.8 Tf [(A number of behavioral and pharmacological manipulations known to delay the progression of neurodegenerative disorders )] TJ ET BT 26.250 111.461 Td /F1 9.8 Tf [(were tested, with the goal of rescuing the deficits in glutamatergic synaptic activity along the corticostriatal pathway in the R6/2 )] TJ ET BT 26.250 99.556 Td /F1 9.8 Tf [(mouse model of HD. Each of these manipulations produced some of the desired effects, but only in a partial manner and in )] TJ ET BT 26.250 87.651 Td /F1 9.8 Tf [(some cases with the potential of inducing adverse reactions.)] TJ ET BT 26.250 68.247 Td /F4 9.8 Tf [(Exercise:)] TJ ET BT 26.250 48.842 Td /F1 9.8 Tf [(Physical activity has shown promising effects in a number of neurodegenerative disorders including PD, AD, as well as other )] TJ ET BT 26.250 36.937 Td /F1 9.8 Tf [(pathologies. When associated with an enriched environment, exercise can delay progression of the phenotype and reduce the )] TJ ET Q q 15.000 22.651 577.500 754.349 re W n 0.965 0.965 0.965 rg 26.250 613.387 555.000 163.613 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 613.387 m 581.250 613.387 l 581.250 614.137 l 26.250 614.137 l f q 35.250 624.637 537.000 152.363 re W n 0.271 0.267 0.267 rg BT 35.250 766.011 Td /F4 9.8 Tf [(Fig. 5:)] TJ ET BT 35.250 744.775 Td /F4 9.8 Tf [(A.)] TJ ET BT 45.000 744.775 Td /F1 9.8 Tf [( Traces are examples of spontaneous mEPSCs [in the presence of TTX \(1 M\)] recorded in WT and R6/2 mice \(11-12 )] TJ ET BT 35.250 731.038 Td /F1 9.8 Tf [(weeks of age\) in the absence \(left\) or presence of a low \(20 mM, middle\) and a high concentration \(100 mM, right\) of )] TJ ET BT 35.250 717.302 Td /F1 9.8 Tf [(Cx614. )] TJ ET BT 68.849 717.302 Td /F4 9.8 Tf [(B.)] TJ ET BT 78.599 717.302 Td /F1 9.8 Tf [( Graphs show concentration-response relationships of average frequencies of spontaneous and mEPSCs )] TJ ET BT 35.250 703.566 Td /F1 9.8 Tf [(between WT and R6/2 mice at 5-7 and 11-12 weeks. Note that the increase in frequency produced at 5-7 weeks by Cx614 )] TJ ET BT 35.250 689.830 Td /F1 9.8 Tf [(is less prominent in cells from both WT and R6/2 mice at 11-12 weeks of age. )] TJ ET BT 372.298 689.830 Td /F4 9.8 Tf [(C.)] TJ ET BT 382.048 689.830 Td /F1 9.8 Tf [( and )] TJ ET BT 403.732 689.830 Td /F4 9.8 Tf [(D.)] TJ ET BT 413.482 689.830 Td /F1 9.8 Tf [( Graphs show amplitude-frequency )] TJ ET BT 35.250 676.093 Td /F1 9.8 Tf [(histograms \( )] TJ ET BT 91.595 676.093 Td /F4 9.8 Tf [(C)] TJ ET BT 98.635 676.093 Td /F1 9.8 Tf [( \) and cumulative probability distributions of inter-event intervals \( )] TJ ET BT 382.028 676.093 Td /F4 9.8 Tf [(D)] TJ ET BT 389.068 676.093 Td /F1 9.8 Tf [( \) of mEPSCs in MSSNs from WT and )] TJ ET BT 35.250 662.357 Td /F1 9.8 Tf [(R6/2 mice before and after Cx614 \(at 11-12 weeks of age\). In spite of an increase in frequency of mEPSCs after Cx614, the )] TJ ET BT 35.250 648.621 Td /F1 9.8 Tf [(difference between WT and R6/2 cells still remains. Line and asterisk indicate statistically significant differences between )] TJ ET BT 35.250 634.885 Td /F1 9.8 Tf [(values for WT and R6/2 mice \(p<0.05-0.001\).)] TJ ET Q BT 26.250 596.364 Td /F1 9.8 Tf [(Cx614 also affected the amplitude and kinetics of spontaneous and mEPSCs. Amplitudes, rise and decay times, as well as half-)] TJ ET BT 26.250 584.459 Td /F1 9.8 Tf [(amplitude durations increased after drug application \(Figure 6A\). These changes in frequency and amplitude/kinetics indicate )] TJ ET BT 26.250 572.554 Td /F1 9.8 Tf [(that Cx614 could have both pre- and post-synaptic effects. In addition to the observed effects on frequency of spontaneous and )] TJ ET BT 26.250 560.649 Td /F1 9.8 Tf [(mEPSCs, in a population of MSSNs from R6/2 mice Cx614, even at low concentrations, induced periodic inward currents )] TJ ET BT 26.250 548.745 Td /F1 9.8 Tf [(accompanied by bursts of high-frequency synaptic activity \(Figure 6B\). These episodes could reflect propagation of burst firing )] TJ ET BT 26.250 536.840 Td /F1 9.8 Tf [(from cortical pyramidal neurons )] TJ ET 0.267 0.267 0.267 rg BT 164.953 536.840 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 175.796 536.840 Td /F1 9.8 Tf [( , as well as increased excitability in cortical neurons in R6/2 mice )] TJ ET 0.267 0.267 0.267 rg BT 460.808 536.840 Td /F1 9.8 Tf [([11])] TJ ET 0.271 0.267 0.267 rg BT 477.070 536.840 Td /F1 9.8 Tf [( .)] TJ ET 0.965 0.965 0.965 rg 26.250 177.541 555.000 349.418 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 526.959 m 581.250 526.959 l 581.250 526.209 l 26.250 526.209 l f 26.250 177.541 m 581.250 177.541 l 581.250 178.291 l 26.250 178.291 l f q 199.500 0 0 225.000 35.250 292.209 cm /I8 Do Q q 35.250 188.791 537.000 97.418 re W n 0.271 0.267 0.267 rg BT 35.250 275.220 Td /F4 9.8 Tf [(Fig. 6:)] TJ ET BT 35.250 253.984 Td /F4 9.8 Tf [(A.)] TJ ET BT 45.000 253.984 Td /F1 9.8 Tf [( Traces are average spontaneous and mEPSCs in TTX and after bath application of increasing concentrations of Cx614. )] TJ ET BT 35.250 240.247 Td /F1 9.8 Tf [(The ampakine increased the amplitude and reduced deactivation of AMPA receptors as indicated by increases in decay )] TJ ET BT 35.250 226.511 Td /F1 9.8 Tf [(time and half-amplitude duration. )] TJ ET BT 179.940 226.511 Td /F4 9.8 Tf [(B.)] TJ ET BT 189.690 226.511 Td /F1 9.8 Tf [( Arrows show large, periodic inward currents were evoked by Cx614 in R6/2 but not WT )] TJ ET BT 35.250 212.775 Td /F1 9.8 Tf [(mice. Representative traces recorded in the presence of Cx614 \(100 mM\) in MSSNs from WT and R6/2 mice at 6-7 and 11-)] TJ ET BT 35.250 199.039 Td /F1 9.8 Tf [(12 weeks.)] TJ ET Q BT 26.250 143.320 Td /F4 12.0 Tf [(Discussion)] TJ ET BT 26.250 123.366 Td /F1 9.8 Tf [(A number of behavioral and pharmacological manipulations known to delay the progression of neurodegenerative disorders )] TJ ET BT 26.250 111.461 Td /F1 9.8 Tf [(were tested, with the goal of rescuing the deficits in glutamatergic synaptic activity along the corticostriatal pathway in the R6/2 )] TJ ET BT 26.250 99.556 Td /F1 9.8 Tf [(mouse model of HD. Each of these manipulations produced some of the desired effects, but only in a partial manner and in )] TJ ET BT 26.250 87.651 Td /F1 9.8 Tf [(some cases with the potential of inducing adverse reactions.)] TJ ET BT 26.250 68.247 Td /F4 9.8 Tf [(Exercise:)] TJ ET BT 26.250 48.842 Td /F1 9.8 Tf [(Physical activity has shown promising effects in a number of neurodegenerative disorders including PD, AD, as well as other )] TJ ET BT 26.250 36.937 Td /F1 9.8 Tf [(pathologies. 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In WT mice, we found that exercise effectively increased synaptic activity in the )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(striatum, indicating that the cortical flow of information is facilitated by physical activity. The fact that both small and large )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(amplitude, action potential-dependent synaptic events in MSSNs were increased probably indicates that the firing of cortical )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(pyramidal neurons also increases after exercise.)] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(As glutamate release can also provide trophic factors, we expected that increased physical activity would rescue the )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(progressive reduction in glutamate activity in R6/2 mice. In contrast, we found that HD mice demonstrated no significant )] TJ ET BT 26.250 688.548 Td /F1 9.8 Tf [(increase in spontaneous synaptic activity. It is possible that this lack of efficacy is associated with the fact that R6/2 mice )] TJ ET BT 26.250 676.643 Td /F1 9.8 Tf [(exercised significantly less that their WT counterparts. It is possible that forced, instead of voluntary, exercise could produce )] TJ ET BT 26.250 664.738 Td /F1 9.8 Tf [(increased synaptic activity. However, such regimen might prove to be stressful and it is known that in R6/2 mice stress can )] TJ ET BT 26.250 652.833 Td /F1 9.8 Tf [(facilitate seizure activity and precipitate death.)] TJ ET BT 26.250 633.429 Td /F1 9.8 Tf [(Interestingly, running in R6/2 mice rescued some biophysical membrane parameters, in particular cell capacitance. The reduced )] TJ ET BT 26.250 621.524 Td /F1 9.8 Tf [(membrane capacitance normally observed in MSSNs from symptomatic R6/2 mice probably reflects a loss of dendritic spines, )] TJ ET BT 26.250 609.619 Td /F1 9.8 Tf [(loss of dendrites, and reduction in somatic area. Running prevented this loss of membrane. 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We have )] TJ ET BT 26.250 514.381 Td /F1 9.8 Tf [(previously provided evidence that the increase in input resistance could be due to a reduction of inwardly rectifying K)] TJ ET BT 528.609 518.269 Td /F1 8.7 Tf [(+)] TJ ET BT 533.670 514.381 Td /F1 9.8 Tf [( channels )] TJ ET 0.267 0.267 0.267 rg BT 26.250 502.476 Td /F1 9.8 Tf [([39])] TJ ET 0.271 0.267 0.267 rg BT 42.513 502.476 Td /F1 9.8 Tf [( combined with the loss of cell membrane. The fact that exercise rescued the loss of membrane but only slightly affected )] TJ ET BT 26.250 490.572 Td /F1 9.8 Tf [(input resistance could indicate that the increase in input resistance depends less on the loss of membrane than it does on )] TJ ET BT 26.250 478.667 Td /F1 9.8 Tf [(reduced expression of inwardly rectifying K)] TJ ET BT 211.568 482.555 Td /F1 8.7 Tf [(+)] TJ ET BT 216.630 478.667 Td /F1 9.8 Tf [( channels.)] TJ ET BT 26.250 459.262 Td /F4 9.8 Tf [(Adenosine:)] TJ ET BT 26.250 439.857 Td /F1 9.8 Tf [(The findings with adenosine emphasize the complexity and multiplicity of effects induced by adenosine receptor activation or )] TJ ET BT 26.250 427.953 Td /F1 9.8 Tf [(blockade, as well as the occurrence of differential effects in control and HD mice. Although some effects appear to be )] TJ ET BT 26.250 416.048 Td /F1 9.8 Tf [(consistent, particularly when EGFP mice are used to identify MSSNs of the indirect pathway, the effects are not very robust and )] TJ ET BT 26.250 404.143 Td /F1 9.8 Tf [(in the case of the antagonist, which has been used as a possible adjuvant in neurodegenerative disorders, the effects on )] TJ ET BT 26.250 392.238 Td /F1 9.8 Tf [(synaptic activity were insignificant. The lack of robust effects of KW 6002 agrees with recent data demonstrating no change in )] TJ ET BT 26.250 380.334 Td /F1 9.8 Tf [(spontaneous EPSCs using two adenosine receptor antagonists, ZM 241385 and ST 1535 )] TJ ET 0.267 0.267 0.267 rg BT 414.836 380.334 Td /F1 9.8 Tf [([43])] TJ ET 0.271 0.267 0.267 rg BT 431.099 380.334 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 360.929 Td /F1 9.8 Tf [(More surprising was the effect the A)] TJ ET BT 181.772 358.865 Td /F1 8.7 Tf [(2A)] TJ ET BT 192.372 360.929 Td /F1 9.8 Tf [( receptor agonist, which effectively restored the excitatory synaptic activity in )] TJ ET BT 26.250 349.024 Td /F1 9.8 Tf [(symptomatic R6/2 mice but produced little effect in WTs. This finding indicates that the progressive reduction in synaptic activity )] TJ ET BT 26.250 337.119 Td /F1 9.8 Tf [(is not the passive consequence of loss of synaptic contacts but active inhibitory mechanisms also are involved. The restoration )] TJ ET BT 26.250 325.215 Td /F1 9.8 Tf [(of excitatory synaptic activity by activation of A)] TJ ET BT 226.749 323.150 Td /F1 8.7 Tf [(2A)] TJ ET BT 237.348 325.215 Td /F1 9.8 Tf [( receptors could be beneficial in the late stages of the disease.)] TJ ET BT 26.250 305.810 Td /F4 9.8 Tf [(Ampakines:)] TJ ET BT 26.250 286.405 Td /F1 9.8 Tf [(The efficacy of Cx614 to increase EPSC frequency and amplitude of spontaneous synaptic currents along the corticostriatal )] TJ ET BT 26.250 274.500 Td /F1 9.8 Tf [(pathway was observed in both WT and R6/2 mice. This effect was age-dependent and appeared to be less robust at 11-12 )] TJ ET BT 26.250 262.596 Td /F1 9.8 Tf [(weeks in both groups, but particularly in MSSNs from R6/2 mice. The increase in EPSC frequency was concentration-)] TJ ET BT 26.250 250.691 Td /F1 9.8 Tf [(dependent and occurred in a range of 20 to 200 M. This compound also affected the kinetics of the currents suggesting both )] TJ ET BT 26.250 238.786 Td /F1 9.8 Tf [(pre- and post-synaptic effects.)] TJ ET BT 26.250 219.381 Td /F1 9.8 Tf [(An unexpected finding was the exacerbation of bursting activity and the induction of large, periodic inward currents which )] TJ ET BT 26.250 207.477 Td /F1 9.8 Tf [(probably reflect cortical synchronization and hyperexcitability in R6/2 MSSNs )] TJ ET 0.267 0.267 0.267 rg BT 360.031 207.477 Td /F1 9.8 Tf [([9])] TJ ET BT 370.873 207.477 Td /F1 9.8 Tf [([11])] TJ ET 0.271 0.267 0.267 rg BT 387.136 207.477 Td /F1 9.8 Tf [( . Although the use of Cx614 in the R6/2 )] TJ ET BT 26.250 195.572 Td /F1 9.8 Tf [(model, which also is considered a model of juvenile HD, could potentially exacerbate seizure propensity, in other models, such )] TJ ET BT 26.250 183.667 Td /F1 9.8 Tf [(as knock-in mice, this compound would not involve the same risk. We have demonstrated that seizure susceptibility after )] TJ ET BT 26.250 171.762 Td /F1 9.8 Tf [(administration of proconvulsant agents such as picrotoxin is not increased in knock-in mice )] TJ ET 0.267 0.267 0.267 rg BT 420.199 171.762 Td /F1 9.8 Tf [([11])] TJ ET 0.271 0.267 0.267 rg BT 436.462 171.762 Td /F1 9.8 Tf [( . More studies using systemic )] TJ ET BT 26.250 159.858 Td /F1 9.8 Tf [(administration of ampakines )] TJ ET BT 150.338 159.858 Td /F5 9.8 Tf [(in vivo)] TJ ET BT 177.970 159.858 Td /F1 9.8 Tf [( are necessary to determine if there are potential negative effects in R6/2 mice. Thus, Cx614 )] TJ ET BT 26.250 147.953 Td /F1 9.8 Tf [(could help reverse the progressive disconnection between cortex and striatum observed in HD mouse models and, at low )] TJ ET BT 26.250 136.048 Td /F1 9.8 Tf [(concentrations, or in adult-onset HD, could be an effective treatment to ameliorate the motor and cognitive phenotype.)] TJ ET BT 26.250 116.643 Td /F1 9.8 Tf [(One limitation of the present study is that transgenic mice had variable repeat lengths. However, in our hands, decreases in )] TJ ET BT 26.250 104.739 Td /F1 9.8 Tf [(spontaneous EPSCs are very similar in R6/2 mice with either ~110 or 150 CAG repeats )] TJ ET 0.267 0.267 0.267 rg BT 405.837 104.739 Td /F1 9.8 Tf [([44])] TJ ET 0.271 0.267 0.267 rg BT 422.100 104.739 Td /F1 9.8 Tf [( and these animals were used to )] TJ ET BT 26.250 92.834 Td /F1 9.8 Tf [(examine the effects of exercise and A)] TJ ET BT 188.831 90.770 Td /F1 8.7 Tf [(2A)] TJ ET BT 199.431 92.834 Td /F1 9.8 Tf [( receptor modulation. The behavioral and electrophysiological phenotypes in mice with )] TJ ET BT 26.250 80.929 Td /F1 9.8 Tf [(~210 CAG repeats are less severe than in the original mice with ~150 CAG repeats and are well suited to examine the effects of )] TJ ET BT 26.250 69.024 Td /F1 9.8 Tf [(the ampakines. In contrast, mice with >220 CAG repeats, which were not used in the present study, display delayed )] TJ ET BT 26.250 57.120 Td /F1 9.8 Tf [(development of the phenotype )] TJ ET 0.267 0.267 0.267 rg BT 160.127 57.120 Td /F1 9.8 Tf [([45])] TJ ET BT 176.390 57.120 Td /F1 9.8 Tf [([46])] TJ ET 0.271 0.267 0.267 rg BT 192.653 57.120 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 37.715 Td /F1 9.8 Tf [(In conclusion, the present studies highlight some of the potential targets and treatments for a specific phenotype; the )] TJ ET Q q 15.000 23.429 577.500 753.571 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(spine loss observed in HD mouse models )] TJ ET 0.267 0.267 0.267 rg BT 208.312 767.476 Td /F1 9.8 Tf [([23])] TJ ET 0.271 0.267 0.267 rg BT 224.575 767.476 Td /F1 9.8 Tf [( . In WT mice, we found that exercise effectively increased synaptic activity in the )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(striatum, indicating that the cortical flow of information is facilitated by physical activity. The fact that both small and large )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(amplitude, action potential-dependent synaptic events in MSSNs were increased probably indicates that the firing of cortical )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(pyramidal neurons also increases after exercise.)] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(As glutamate release can also provide trophic factors, we expected that increased physical activity would rescue the )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(progressive reduction in glutamate activity in R6/2 mice. In contrast, we found that HD mice demonstrated no significant )] TJ ET BT 26.250 688.548 Td /F1 9.8 Tf [(increase in spontaneous synaptic activity. It is possible that this lack of efficacy is associated with the fact that R6/2 mice )] TJ ET BT 26.250 676.643 Td /F1 9.8 Tf [(exercised significantly less that their WT counterparts. It is possible that forced, instead of voluntary, exercise could produce )] TJ ET BT 26.250 664.738 Td /F1 9.8 Tf [(increased synaptic activity. However, such regimen might prove to be stressful and it is known that in R6/2 mice stress can )] TJ ET BT 26.250 652.833 Td /F1 9.8 Tf [(facilitate seizure activity and precipitate death.)] TJ ET BT 26.250 633.429 Td /F1 9.8 Tf [(Interestingly, running in R6/2 mice rescued some biophysical membrane parameters, in particular cell capacitance. The reduced )] TJ ET BT 26.250 621.524 Td /F1 9.8 Tf [(membrane capacitance normally observed in MSSNs from symptomatic R6/2 mice probably reflects a loss of dendritic spines, )] TJ ET BT 26.250 609.619 Td /F1 9.8 Tf [(loss of dendrites, and reduction in somatic area. Running prevented this loss of membrane. As exercise increases BDNF )] TJ ET BT 26.250 597.714 Td /F1 9.8 Tf [(production )] TJ ET 0.267 0.267 0.267 rg BT 74.483 597.714 Td /F1 9.8 Tf [([20])] TJ ET 0.271 0.267 0.267 rg BT 90.746 597.714 Td /F1 9.8 Tf [( and BDNF can reduce the severity of HD symptoms )] TJ ET 0.267 0.267 0.267 rg BT 319.949 597.714 Td /F1 9.8 Tf [([40])] TJ ET 0.271 0.267 0.267 rg BT 336.212 597.714 Td /F1 9.8 Tf [( , it is possible that in running R6/2 mice BDNF helps to )] TJ ET BT 26.250 585.810 Td /F1 9.8 Tf [(maintain cellular integrity. BDNF determination in running and non-running mice did not reveal significant increases in protein )] TJ ET BT 26.250 573.905 Td /F1 9.8 Tf [(content in soluble extracts from the striatum of R6/2 mice, consistent with a previous report )] TJ ET 0.267 0.267 0.267 rg BT 420.199 573.905 Td /F1 9.8 Tf [([41])] TJ ET 0.271 0.267 0.267 rg BT 436.462 573.905 Td /F1 9.8 Tf [( . However, because the ELISA )] TJ ET BT 26.250 562.000 Td /F1 9.8 Tf [(assay does not differentiate between the more abundant pro-isoforms of BDNF and its mature processed form, we cannot rule )] TJ ET BT 26.250 550.095 Td /F1 9.8 Tf [(out lower levels of mature BDNF that went undetected. This would be especially true for mature BDNF released at corticostriatal )] TJ ET BT 26.250 538.191 Td /F1 9.8 Tf [(synapses )] TJ ET 0.267 0.267 0.267 rg BT 70.144 538.191 Td /F1 9.8 Tf [([42])] TJ ET 0.271 0.267 0.267 rg BT 86.407 538.191 Td /F1 9.8 Tf [( , which would require more refined measurements in subcellular synaptic fractions. There is also the possibility )] TJ ET BT 26.250 526.286 Td /F1 9.8 Tf [(that exercise can exert protective effects independent of BDNF and/or that other trophic factors are involved. We have )] TJ ET BT 26.250 514.381 Td /F1 9.8 Tf [(previously provided evidence that the increase in input resistance could be due to a reduction of inwardly rectifying K)] TJ ET BT 528.609 518.269 Td /F1 8.7 Tf [(+)] TJ ET BT 533.670 514.381 Td /F1 9.8 Tf [( channels )] TJ ET 0.267 0.267 0.267 rg BT 26.250 502.476 Td /F1 9.8 Tf [([39])] TJ ET 0.271 0.267 0.267 rg BT 42.513 502.476 Td /F1 9.8 Tf [( combined with the loss of cell membrane. The fact that exercise rescued the loss of membrane but only slightly affected )] TJ ET BT 26.250 490.572 Td /F1 9.8 Tf [(input resistance could indicate that the increase in input resistance depends less on the loss of membrane than it does on )] TJ ET BT 26.250 478.667 Td /F1 9.8 Tf [(reduced expression of inwardly rectifying K)] TJ ET BT 211.568 482.555 Td /F1 8.7 Tf [(+)] TJ ET BT 216.630 478.667 Td /F1 9.8 Tf [( channels.)] TJ ET BT 26.250 459.262 Td /F4 9.8 Tf [(Adenosine:)] TJ ET BT 26.250 439.857 Td /F1 9.8 Tf [(The findings with adenosine emphasize the complexity and multiplicity of effects induced by adenosine receptor activation or )] TJ ET BT 26.250 427.953 Td /F1 9.8 Tf [(blockade, as well as the occurrence of differential effects in control and HD mice. Although some effects appear to be )] TJ ET BT 26.250 416.048 Td /F1 9.8 Tf [(consistent, particularly when EGFP mice are used to identify MSSNs of the indirect pathway, the effects are not very robust and )] TJ ET BT 26.250 404.143 Td /F1 9.8 Tf [(in the case of the antagonist, which has been used as a possible adjuvant in neurodegenerative disorders, the effects on )] TJ ET BT 26.250 392.238 Td /F1 9.8 Tf [(synaptic activity were insignificant. The lack of robust effects of KW 6002 agrees with recent data demonstrating no change in )] TJ ET BT 26.250 380.334 Td /F1 9.8 Tf [(spontaneous EPSCs using two adenosine receptor antagonists, ZM 241385 and ST 1535 )] TJ ET 0.267 0.267 0.267 rg BT 414.836 380.334 Td /F1 9.8 Tf [([43])] TJ ET 0.271 0.267 0.267 rg BT 431.099 380.334 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 360.929 Td /F1 9.8 Tf [(More surprising was the effect the A)] TJ ET BT 181.772 358.865 Td /F1 8.7 Tf [(2A)] TJ ET BT 192.372 360.929 Td /F1 9.8 Tf [( receptor agonist, which effectively restored the excitatory synaptic activity in )] TJ ET BT 26.250 349.024 Td /F1 9.8 Tf [(symptomatic R6/2 mice but produced little effect in WTs. This finding indicates that the progressive reduction in synaptic activity )] TJ ET BT 26.250 337.119 Td /F1 9.8 Tf [(is not the passive consequence of loss of synaptic contacts but active inhibitory mechanisms also are involved. The restoration )] TJ ET BT 26.250 325.215 Td /F1 9.8 Tf [(of excitatory synaptic activity by activation of A)] TJ ET BT 226.749 323.150 Td /F1 8.7 Tf [(2A)] TJ ET BT 237.348 325.215 Td /F1 9.8 Tf [( receptors could be beneficial in the late stages of the disease.)] TJ ET BT 26.250 305.810 Td /F4 9.8 Tf [(Ampakines:)] TJ ET BT 26.250 286.405 Td /F1 9.8 Tf [(The efficacy of Cx614 to increase EPSC frequency and amplitude of spontaneous synaptic currents along the corticostriatal )] TJ ET BT 26.250 274.500 Td /F1 9.8 Tf [(pathway was observed in both WT and R6/2 mice. This effect was age-dependent and appeared to be less robust at 11-12 )] TJ ET BT 26.250 262.596 Td /F1 9.8 Tf [(weeks in both groups, but particularly in MSSNs from R6/2 mice. The increase in EPSC frequency was concentration-)] TJ ET BT 26.250 250.691 Td /F1 9.8 Tf [(dependent and occurred in a range of 20 to 200 M. This compound also affected the kinetics of the currents suggesting both )] TJ ET BT 26.250 238.786 Td /F1 9.8 Tf [(pre- and post-synaptic effects.)] TJ ET BT 26.250 219.381 Td /F1 9.8 Tf [(An unexpected finding was the exacerbation of bursting activity and the induction of large, periodic inward currents which )] TJ ET BT 26.250 207.477 Td /F1 9.8 Tf [(probably reflect cortical synchronization and hyperexcitability in R6/2 MSSNs )] TJ ET 0.267 0.267 0.267 rg BT 360.031 207.477 Td /F1 9.8 Tf [([9])] TJ ET BT 370.873 207.477 Td /F1 9.8 Tf [([11])] TJ ET 0.271 0.267 0.267 rg BT 387.136 207.477 Td /F1 9.8 Tf [( . Although the use of Cx614 in the R6/2 )] TJ ET BT 26.250 195.572 Td /F1 9.8 Tf [(model, which also is considered a model of juvenile HD, could potentially exacerbate seizure propensity, in other models, such )] TJ ET BT 26.250 183.667 Td /F1 9.8 Tf [(as knock-in mice, this compound would not involve the same risk. We have demonstrated that seizure susceptibility after )] TJ ET BT 26.250 171.762 Td /F1 9.8 Tf [(administration of proconvulsant agents such as picrotoxin is not increased in knock-in mice )] TJ ET 0.267 0.267 0.267 rg BT 420.199 171.762 Td /F1 9.8 Tf [([11])] TJ ET 0.271 0.267 0.267 rg BT 436.462 171.762 Td /F1 9.8 Tf [( . More studies using systemic )] TJ ET BT 26.250 159.858 Td /F1 9.8 Tf [(administration of ampakines )] TJ ET BT 150.338 159.858 Td /F5 9.8 Tf [(in vivo)] TJ ET BT 177.970 159.858 Td /F1 9.8 Tf [( are necessary to determine if there are potential negative effects in R6/2 mice. Thus, Cx614 )] TJ ET BT 26.250 147.953 Td /F1 9.8 Tf [(could help reverse the progressive disconnection between cortex and striatum observed in HD mouse models and, at low )] TJ ET BT 26.250 136.048 Td /F1 9.8 Tf [(concentrations, or in adult-onset HD, could be an effective treatment to ameliorate the motor and cognitive phenotype.)] TJ ET BT 26.250 116.643 Td /F1 9.8 Tf [(One limitation of the present study is that transgenic mice had variable repeat lengths. However, in our hands, decreases in )] TJ ET BT 26.250 104.739 Td /F1 9.8 Tf [(spontaneous EPSCs are very similar in R6/2 mice with either ~110 or 150 CAG repeats )] TJ ET 0.267 0.267 0.267 rg BT 405.837 104.739 Td /F1 9.8 Tf [([44])] TJ ET 0.271 0.267 0.267 rg BT 422.100 104.739 Td /F1 9.8 Tf [( and these animals were used to )] TJ ET BT 26.250 92.834 Td /F1 9.8 Tf [(examine the effects of exercise and A)] TJ ET BT 188.831 90.770 Td /F1 8.7 Tf [(2A)] TJ ET BT 199.431 92.834 Td /F1 9.8 Tf [( receptor modulation. The behavioral and electrophysiological phenotypes in mice with )] TJ ET BT 26.250 80.929 Td /F1 9.8 Tf [(~210 CAG repeats are less severe than in the original mice with ~150 CAG repeats and are well suited to examine the effects of )] TJ ET BT 26.250 69.024 Td /F1 9.8 Tf [(the ampakines. In contrast, mice with >220 CAG repeats, which were not used in the present study, display delayed )] TJ ET BT 26.250 57.120 Td /F1 9.8 Tf [(development of the phenotype )] TJ ET 0.267 0.267 0.267 rg BT 160.127 57.120 Td /F1 9.8 Tf [([45])] TJ ET BT 176.390 57.120 Td /F1 9.8 Tf [([46])] TJ ET 0.271 0.267 0.267 rg BT 192.653 57.120 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 37.715 Td /F1 9.8 Tf [(In conclusion, the present studies highlight some of the potential targets and treatments for a specific phenotype; the )] TJ ET Q q 15.000 23.429 577.500 753.571 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(spine loss observed in HD mouse models )] TJ ET 0.267 0.267 0.267 rg BT 208.312 767.476 Td /F1 9.8 Tf [([23])] TJ ET 0.271 0.267 0.267 rg BT 224.575 767.476 Td /F1 9.8 Tf [( . In WT mice, we found that exercise effectively increased synaptic activity in the )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(striatum, indicating that the cortical flow of information is facilitated by physical activity. The fact that both small and large )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(amplitude, action potential-dependent synaptic events in MSSNs were increased probably indicates that the firing of cortical )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(pyramidal neurons also increases after exercise.)] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(As glutamate release can also provide trophic factors, we expected that increased physical activity would rescue the )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(progressive reduction in glutamate activity in R6/2 mice. In contrast, we found that HD mice demonstrated no significant )] TJ ET BT 26.250 688.548 Td /F1 9.8 Tf [(increase in spontaneous synaptic activity. It is possible that this lack of efficacy is associated with the fact that R6/2 mice )] TJ ET BT 26.250 676.643 Td /F1 9.8 Tf [(exercised significantly less that their WT counterparts. It is possible that forced, instead of voluntary, exercise could produce )] TJ ET BT 26.250 664.738 Td /F1 9.8 Tf [(increased synaptic activity. However, such regimen might prove to be stressful and it is known that in R6/2 mice stress can )] TJ ET BT 26.250 652.833 Td /F1 9.8 Tf [(facilitate seizure activity and precipitate death.)] TJ ET BT 26.250 633.429 Td /F1 9.8 Tf [(Interestingly, running in R6/2 mice rescued some biophysical membrane parameters, in particular cell capacitance. The reduced )] TJ ET BT 26.250 621.524 Td /F1 9.8 Tf [(membrane capacitance normally observed in MSSNs from symptomatic R6/2 mice probably reflects a loss of dendritic spines, )] TJ ET BT 26.250 609.619 Td /F1 9.8 Tf [(loss of dendrites, and reduction in somatic area. Running prevented this loss of membrane. As exercise increases BDNF )] TJ ET BT 26.250 597.714 Td /F1 9.8 Tf [(production )] TJ ET 0.267 0.267 0.267 rg BT 74.483 597.714 Td /F1 9.8 Tf [([20])] TJ ET 0.271 0.267 0.267 rg BT 90.746 597.714 Td /F1 9.8 Tf [( and BDNF can reduce the severity of HD symptoms )] TJ ET 0.267 0.267 0.267 rg BT 319.949 597.714 Td /F1 9.8 Tf [([40])] TJ ET 0.271 0.267 0.267 rg BT 336.212 597.714 Td /F1 9.8 Tf [( , it is possible that in running R6/2 mice BDNF helps to )] TJ ET BT 26.250 585.810 Td /F1 9.8 Tf [(maintain cellular integrity. BDNF determination in running and non-running mice did not reveal significant increases in protein )] TJ ET BT 26.250 573.905 Td /F1 9.8 Tf [(content in soluble extracts from the striatum of R6/2 mice, consistent with a previous report )] TJ ET 0.267 0.267 0.267 rg BT 420.199 573.905 Td /F1 9.8 Tf [([41])] TJ ET 0.271 0.267 0.267 rg BT 436.462 573.905 Td /F1 9.8 Tf [( . However, because the ELISA )] TJ ET BT 26.250 562.000 Td /F1 9.8 Tf [(assay does not differentiate between the more abundant pro-isoforms of BDNF and its mature processed form, we cannot rule )] TJ ET BT 26.250 550.095 Td /F1 9.8 Tf [(out lower levels of mature BDNF that went undetected. This would be especially true for mature BDNF released at corticostriatal )] TJ ET BT 26.250 538.191 Td /F1 9.8 Tf [(synapses )] TJ ET 0.267 0.267 0.267 rg BT 70.144 538.191 Td /F1 9.8 Tf [([42])] TJ ET 0.271 0.267 0.267 rg BT 86.407 538.191 Td /F1 9.8 Tf [( , which would require more refined measurements in subcellular synaptic fractions. There is also the possibility )] TJ ET BT 26.250 526.286 Td /F1 9.8 Tf [(that exercise can exert protective effects independent of BDNF and/or that other trophic factors are involved. We have )] TJ ET BT 26.250 514.381 Td /F1 9.8 Tf [(previously provided evidence that the increase in input resistance could be due to a reduction of inwardly rectifying K)] TJ ET BT 528.609 518.269 Td /F1 8.7 Tf [(+)] TJ ET BT 533.670 514.381 Td /F1 9.8 Tf [( channels )] TJ ET 0.267 0.267 0.267 rg BT 26.250 502.476 Td /F1 9.8 Tf [([39])] TJ ET 0.271 0.267 0.267 rg BT 42.513 502.476 Td /F1 9.8 Tf [( combined with the loss of cell membrane. The fact that exercise rescued the loss of membrane but only slightly affected )] TJ ET BT 26.250 490.572 Td /F1 9.8 Tf [(input resistance could indicate that the increase in input resistance depends less on the loss of membrane than it does on )] TJ ET BT 26.250 478.667 Td /F1 9.8 Tf [(reduced expression of inwardly rectifying K)] TJ ET BT 211.568 482.555 Td /F1 8.7 Tf [(+)] TJ ET BT 216.630 478.667 Td /F1 9.8 Tf [( channels.)] TJ ET BT 26.250 459.262 Td /F4 9.8 Tf [(Adenosine:)] TJ ET BT 26.250 439.857 Td /F1 9.8 Tf [(The findings with adenosine emphasize the complexity and multiplicity of effects induced by adenosine receptor activation or )] TJ ET BT 26.250 427.953 Td /F1 9.8 Tf [(blockade, as well as the occurrence of differential effects in control and HD mice. Although some effects appear to be )] TJ ET BT 26.250 416.048 Td /F1 9.8 Tf [(consistent, particularly when EGFP mice are used to identify MSSNs of the indirect pathway, the effects are not very robust and )] TJ ET BT 26.250 404.143 Td /F1 9.8 Tf [(in the case of the antagonist, which has been used as a possible adjuvant in neurodegenerative disorders, the effects on )] TJ ET BT 26.250 392.238 Td /F1 9.8 Tf [(synaptic activity were insignificant. The lack of robust effects of KW 6002 agrees with recent data demonstrating no change in )] TJ ET BT 26.250 380.334 Td /F1 9.8 Tf [(spontaneous EPSCs using two adenosine receptor antagonists, ZM 241385 and ST 1535 )] TJ ET 0.267 0.267 0.267 rg BT 414.836 380.334 Td /F1 9.8 Tf [([43])] TJ ET 0.271 0.267 0.267 rg BT 431.099 380.334 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 360.929 Td /F1 9.8 Tf [(More surprising was the effect the A)] TJ ET BT 181.772 358.865 Td /F1 8.7 Tf [(2A)] TJ ET BT 192.372 360.929 Td /F1 9.8 Tf [( receptor agonist, which effectively restored the excitatory synaptic activity in )] TJ ET BT 26.250 349.024 Td /F1 9.8 Tf [(symptomatic R6/2 mice but produced little effect in WTs. This finding indicates that the progressive reduction in synaptic activity )] TJ ET BT 26.250 337.119 Td /F1 9.8 Tf [(is not the passive consequence of loss of synaptic contacts but active inhibitory mechanisms also are involved. The restoration )] TJ ET BT 26.250 325.215 Td /F1 9.8 Tf [(of excitatory synaptic activity by activation of A)] TJ ET BT 226.749 323.150 Td /F1 8.7 Tf [(2A)] TJ ET BT 237.348 325.215 Td /F1 9.8 Tf [( receptors could be beneficial in the late stages of the disease.)] TJ ET BT 26.250 305.810 Td /F4 9.8 Tf [(Ampakines:)] TJ ET BT 26.250 286.405 Td /F1 9.8 Tf [(The efficacy of Cx614 to increase EPSC frequency and amplitude of spontaneous synaptic currents along the corticostriatal )] TJ ET BT 26.250 274.500 Td /F1 9.8 Tf [(pathway was observed in both WT and R6/2 mice. This effect was age-dependent and appeared to be less robust at 11-12 )] TJ ET BT 26.250 262.596 Td /F1 9.8 Tf [(weeks in both groups, but particularly in MSSNs from R6/2 mice. The increase in EPSC frequency was concentration-)] TJ ET BT 26.250 250.691 Td /F1 9.8 Tf [(dependent and occurred in a range of 20 to 200 M. This compound also affected the kinetics of the currents suggesting both )] TJ ET BT 26.250 238.786 Td /F1 9.8 Tf [(pre- and post-synaptic effects.)] TJ ET BT 26.250 219.381 Td /F1 9.8 Tf [(An unexpected finding was the exacerbation of bursting activity and the induction of large, periodic inward currents which )] TJ ET BT 26.250 207.477 Td /F1 9.8 Tf [(probably reflect cortical synchronization and hyperexcitability in R6/2 MSSNs )] TJ ET 0.267 0.267 0.267 rg BT 360.031 207.477 Td /F1 9.8 Tf [([9])] TJ ET BT 370.873 207.477 Td /F1 9.8 Tf [([11])] TJ ET 0.271 0.267 0.267 rg BT 387.136 207.477 Td /F1 9.8 Tf [( . Although the use of Cx614 in the R6/2 )] TJ ET BT 26.250 195.572 Td /F1 9.8 Tf [(model, which also is considered a model of juvenile HD, could potentially exacerbate seizure propensity, in other models, such )] TJ ET BT 26.250 183.667 Td /F1 9.8 Tf [(as knock-in mice, this compound would not involve the same risk. We have demonstrated that seizure susceptibility after )] TJ ET BT 26.250 171.762 Td /F1 9.8 Tf [(administration of proconvulsant agents such as picrotoxin is not increased in knock-in mice )] TJ ET 0.267 0.267 0.267 rg BT 420.199 171.762 Td /F1 9.8 Tf [([11])] TJ ET 0.271 0.267 0.267 rg BT 436.462 171.762 Td /F1 9.8 Tf [( . More studies using systemic )] TJ ET BT 26.250 159.858 Td /F1 9.8 Tf [(administration of ampakines )] TJ ET BT 150.338 159.858 Td /F5 9.8 Tf [(in vivo)] TJ ET BT 177.970 159.858 Td /F1 9.8 Tf [( are necessary to determine if there are potential negative effects in R6/2 mice. Thus, Cx614 )] TJ ET BT 26.250 147.953 Td /F1 9.8 Tf [(could help reverse the progressive disconnection between cortex and striatum observed in HD mouse models and, at low )] TJ ET BT 26.250 136.048 Td /F1 9.8 Tf [(concentrations, or in adult-onset HD, could be an effective treatment to ameliorate the motor and cognitive phenotype.)] TJ ET BT 26.250 116.643 Td /F1 9.8 Tf [(One limitation of the present study is that transgenic mice had variable repeat lengths. However, in our hands, decreases in )] TJ ET BT 26.250 104.739 Td /F1 9.8 Tf [(spontaneous EPSCs are very similar in R6/2 mice with either ~110 or 150 CAG repeats )] TJ ET 0.267 0.267 0.267 rg BT 405.837 104.739 Td /F1 9.8 Tf [([44])] TJ ET 0.271 0.267 0.267 rg BT 422.100 104.739 Td /F1 9.8 Tf [( and these animals were used to )] TJ ET BT 26.250 92.834 Td /F1 9.8 Tf [(examine the effects of exercise and A)] TJ ET BT 188.831 90.770 Td /F1 8.7 Tf [(2A)] TJ ET BT 199.431 92.834 Td /F1 9.8 Tf [( receptor modulation. The behavioral and electrophysiological phenotypes in mice with )] TJ ET BT 26.250 80.929 Td /F1 9.8 Tf [(~210 CAG repeats are less severe than in the original mice with ~150 CAG repeats and are well suited to examine the effects of )] TJ ET BT 26.250 69.024 Td /F1 9.8 Tf [(the ampakines. In contrast, mice with >220 CAG repeats, which were not used in the present study, display delayed )] TJ ET BT 26.250 57.120 Td /F1 9.8 Tf [(development of the phenotype )] TJ ET 0.267 0.267 0.267 rg BT 160.127 57.120 Td /F1 9.8 Tf [([45])] TJ ET BT 176.390 57.120 Td /F1 9.8 Tf [([46])] TJ ET 0.271 0.267 0.267 rg BT 192.653 57.120 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 37.715 Td /F1 9.8 Tf [(In conclusion, the present studies highlight some of the potential targets and treatments for a specific phenotype; the )] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(9)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 439 0 obj << /Type /Annot /Subtype /Link /A 440 0 R /Border [0 0 0] /H /I /Rect [ 208.3117 766.5743 224.5747 776.4950 ] >> endobj 440 0 obj << /Type /Action >> endobj 441 0 obj << /Type /Annot /Subtype /Link /A 442 0 R /Border [0 0 0] /H /I /Rect [ 74.4832 596.8126 90.7463 606.7332 ] >> endobj 442 0 obj << /Type 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/Action >> endobj 515 0 obj << /Type /Annot /Subtype /Link /A 516 0 R /Border [0 0 0] /H /I /Rect [ 176.3903 56.2178 192.6533 66.1385 ] >> endobj 516 0 obj << /Type /Action >> endobj 517 0 obj << /Type /Page /Parent 3 0 R /Contents 518 0 R >> endobj 518 0 obj << /Length 20492 >> stream 0.271 0.267 0.267 rg q 15.000 38.045 577.500 738.955 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(progressive disconnection between cortex and striatum, which may be responsible for late HD symptoms. Each manipulation )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(had different success rates depending on the disease stage, suggesting that careful monitoring of patient disease stage is )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(necessary for design of treatment regimens. In addition, our data suggest that both physical activity and polypharmacy may be )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(indicated in order to slow the progression of HD. All of these treatments ameliorated or reversed the electrophysiological )] TJ ET BT 26.250 719.857 Td /F1 9.8 Tf [(abnormalities. However, further research is required to reduce potential negative side effects of these agents.)] TJ ET BT 26.250 683.255 Td /F4 12.0 Tf [(Competing Interests)] TJ ET BT 26.250 663.300 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 626.698 Td /F4 12.0 Tf [(Acknowledgements)] TJ ET BT 26.250 606.744 Td /F1 9.8 Tf [(We would like to acknowledge Irene Yamazaki, Nanping Wu, Joshua L. Plotkin, Behnoud Beroukhim and Xiaoping Sun for their )] TJ ET BT 26.250 594.839 Td /F1 9.8 Tf [(help in data gathering and analysis. We also thank Donna Crandall for her help with the figures.)] TJ ET BT 26.250 565.736 Td /F4 12.0 Tf [(References)] TJ ET BT 26.250 538.282 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 538.282 Td /F1 9.8 Tf [(The Huntington's Disease Collaborative Research Group \(1993\) A novel gene containing a trinucleotide repeat that is )] TJ ET BT 26.250 526.377 Td /F1 9.8 Tf [(expanded and unstable on Huntington's disease chromosomes. Cell 72:971-983.)] TJ ET BT 26.250 506.973 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 506.973 Td /F1 9.8 Tf [(Vonsattel JP, DiFiglia M \(1998\) Huntington disease. J Neuropathol Exp Neurol 57:369-384.)] TJ ET BT 26.250 487.568 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 487.568 Td /F1 9.8 Tf [(Bates G, Harper PS, Jones L \(2002\) Huntington's disease, 3rd Edition. Oxford ; New York: Oxford University Press.)] TJ ET BT 26.250 468.163 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 468.163 Td /F1 9.8 Tf [(Levine MS, Cepeda C, Hickey MA, Fleming SM, Chesselet MF \(2004\) Genetic mouse models of Huntington's and )] TJ ET BT 26.250 456.258 Td /F1 9.8 Tf [(Parkinson's diseases: illuminating but imperfect. Trends Neurosci 27:691-697.)] TJ ET BT 26.250 436.854 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 436.854 Td /F1 9.8 Tf [(Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW, )] TJ ET BT 26.250 424.949 Td /F1 9.8 Tf [(Bates GP \(1996\) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological )] TJ ET BT 26.250 413.044 Td /F1 9.8 Tf [(phenotype in transgenic mice. Cell 87:493-506.)] TJ ET BT 26.250 393.639 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 393.639 Td /F1 9.8 Tf [(Cepeda C, Wu N, Andr VM, Cummings DM, Levine MS \(2007\) The corticostriatal pathway in Huntington's disease. Prog )] TJ ET BT 26.250 381.735 Td /F1 9.8 Tf [(Neuorbiol 81:253-271.)] TJ ET BT 26.250 362.330 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 362.330 Td /F1 9.8 Tf [(Cepeda C, Cummings DM, Andre VM, Holley SM, Levine MS \(2010\) Genetic mouse models of Huntington's disease: focus )] TJ ET BT 26.250 350.425 Td /F1 9.8 Tf [(on electrophysiological mechanisms. ASN Neuro 2:e00033.)] TJ ET BT 26.250 331.020 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 331.020 Td /F1 9.8 Tf [(Klapstein GJ, Fisher RS, Zanjani H, Cepeda C, Jokel ES, Chesselet MF, Levine MS \(2001\) Electrophysiological and )] TJ ET BT 26.250 319.116 Td /F1 9.8 Tf [(Morphological Changes in Striatal Spiny Neurons in R6/2 Huntington's Disease Transgenic Mice. J Neurophysiol 86:2667-2677.)] TJ ET BT 26.250 299.711 Td /F1 9.8 Tf [(9.)] TJ ET BT 38.132 299.711 Td /F1 9.8 Tf [(Cepeda C, Hurst RS, Calvert CR, Hernandez-Echeagaray E, Nguyen OK, Jocoy E, Christian LJ, Ariano MA, Levine MS )] TJ ET BT 26.250 287.806 Td /F1 9.8 Tf [(\(2003\) Transient and progressive electrophysiological alterations in the corticostriatal pathway in a mouse model of Huntington's )] TJ ET BT 26.250 275.901 Td /F1 9.8 Tf [(disease. J Neurosci 23:961-969.)] TJ ET BT 26.250 256.497 Td /F1 9.8 Tf [(10.)] TJ ET BT 43.553 256.497 Td /F1 9.8 Tf [(Joshi PR, Wu NP, Andre VM, Cummings DM, Cepeda C, Joyce JA, Carroll JB, Leavitt BR, Hayden MR, Levine MS, )] TJ ET BT 26.250 244.592 Td /F1 9.8 Tf [(Bamford NS \(2009\) Age-dependent alterations of corticostriatal activity in the YAC128 mouse model of Huntington disease. J )] TJ ET BT 26.250 232.687 Td /F1 9.8 Tf [(Neurosci 29:2414-2427.)] TJ ET BT 26.250 213.282 Td /F1 9.8 Tf [(11.)] TJ ET BT 43.553 213.282 Td /F1 9.8 Tf [(Cummings DM, Andre VM, Uzgil BO, Gee SM, Fisher YE, Cepeda C, Levine MS \(2009\) Alterations in cortical excitation and )] TJ ET BT 26.250 201.378 Td /F1 9.8 Tf [(inhibition in genetic mouse models of Huntington's disease. J Neurosci 29:10371-10386.)] TJ ET BT 26.250 181.973 Td /F1 9.8 Tf [(12.)] TJ ET BT 43.553 181.973 Td /F1 9.8 Tf [(Pallier PN, Maywood ES, Zheng Z, Chesham JE, Inyushkin AN, Dyball R, Hastings MH, Morton AJ \(2007\) Pharmacological )] TJ ET BT 26.250 170.068 Td /F1 9.8 Tf [(imposition of sleep slows cognitive decline and reverses dysregulation of circadian gene expression in a transgenic mouse )] TJ ET BT 26.250 158.163 Td /F1 9.8 Tf [(model of Huntington's disease. J Neurosci 27:7869-7878.)] TJ ET BT 26.250 138.759 Td /F1 9.8 Tf [(13.)] TJ ET BT 43.553 138.759 Td /F1 9.8 Tf [(Masuda N, Peng Q, Li Q, Jiang M, Liang Y, Wang X, Zhao M, Wang W, Ross CA, Duan W \(2008\) Tiagabine is )] TJ ET BT 26.250 126.854 Td /F1 9.8 Tf [(neuroprotective in the N171-82Q and R6/2 mouse models of Huntington's disease. Neurobiol Dis 30:293-302.)] TJ ET BT 26.250 107.449 Td /F1 9.8 Tf [(14.)] TJ ET BT 43.553 107.449 Td /F1 9.8 Tf [(Stack EC, Dedeoglu A, Smith KM, Cormier K, Kubilus JK, Bogdanov M, Matson WR,Yang L, Jenkins BG, Luthi-Carter R, )] TJ ET BT 26.250 95.544 Td /F1 9.8 Tf [(Kowall NW, Hersch SM, Beal MF, Ferrante RJ \(2007\) Neuroprotective effects of synaptic modulation in Huntington's disease )] TJ ET BT 26.250 83.640 Td /F1 9.8 Tf [(R6/2 mice. J Neurosci 27:12908-12915.)] TJ ET BT 26.250 64.235 Td /F1 9.8 Tf [(15.)] TJ ET BT 43.553 64.235 Td /F1 9.8 Tf [(Levine MS, Klapstein GJ, Koppel A, Gruen E, Cepeda C, Vargas ME, Jokel ES, Carpenter EM, Zanjani H, Hurst RS, )] TJ ET BT 26.250 52.330 Td /F1 9.8 Tf [(Efstratiadis A, Zeitlin S, Chesselet MF \(1999\) Enhanced sensitivity to N-methyl-D-aspartate receptor activation in transgenic and )] TJ ET Q q 15.000 38.045 577.500 738.955 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(progressive disconnection between cortex and striatum, which may be responsible for late HD symptoms. Each manipulation )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(had different success rates depending on the disease stage, suggesting that careful monitoring of patient disease stage is )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(necessary for design of treatment regimens. In addition, our data suggest that both physical activity and polypharmacy may be )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(indicated in order to slow the progression of HD. All of these treatments ameliorated or reversed the electrophysiological )] TJ ET BT 26.250 719.857 Td /F1 9.8 Tf [(abnormalities. However, further research is required to reduce potential negative side effects of these agents.)] TJ ET BT 26.250 683.255 Td /F4 12.0 Tf [(Competing Interests)] TJ ET BT 26.250 663.300 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 626.698 Td /F4 12.0 Tf [(Acknowledgements)] TJ ET BT 26.250 606.744 Td /F1 9.8 Tf [(We would like to acknowledge Irene Yamazaki, Nanping Wu, Joshua L. Plotkin, Behnoud Beroukhim and Xiaoping Sun for their )] TJ ET BT 26.250 594.839 Td /F1 9.8 Tf [(help in data gathering and analysis. We also thank Donna Crandall for her help with the figures.)] TJ ET BT 26.250 565.736 Td /F4 12.0 Tf [(References)] TJ ET BT 26.250 538.282 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 538.282 Td /F1 9.8 Tf [(The Huntington's Disease Collaborative Research Group \(1993\) A novel gene containing a trinucleotide repeat that is )] TJ ET BT 26.250 526.377 Td /F1 9.8 Tf [(expanded and unstable on Huntington's disease chromosomes. Cell 72:971-983.)] TJ ET BT 26.250 506.973 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 506.973 Td /F1 9.8 Tf [(Vonsattel JP, DiFiglia M \(1998\) Huntington disease. J Neuropathol Exp Neurol 57:369-384.)] TJ ET BT 26.250 487.568 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 487.568 Td /F1 9.8 Tf [(Bates G, Harper PS, Jones L \(2002\) Huntington's disease, 3rd Edition. Oxford ; New York: Oxford University Press.)] TJ ET BT 26.250 468.163 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 468.163 Td /F1 9.8 Tf [(Levine MS, Cepeda C, Hickey MA, Fleming SM, Chesselet MF \(2004\) Genetic mouse models of Huntington's and )] TJ ET BT 26.250 456.258 Td /F1 9.8 Tf [(Parkinson's diseases: illuminating but imperfect. Trends Neurosci 27:691-697.)] TJ ET BT 26.250 436.854 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 436.854 Td /F1 9.8 Tf [(Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW, )] TJ ET BT 26.250 424.949 Td /F1 9.8 Tf [(Bates GP \(1996\) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological )] TJ ET BT 26.250 413.044 Td /F1 9.8 Tf [(phenotype in transgenic mice. Cell 87:493-506.)] TJ ET BT 26.250 393.639 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 393.639 Td /F1 9.8 Tf [(Cepeda C, Wu N, Andr VM, Cummings DM, Levine MS \(2007\) The corticostriatal pathway in Huntington's disease. Prog )] TJ ET BT 26.250 381.735 Td /F1 9.8 Tf [(Neuorbiol 81:253-271.)] TJ ET BT 26.250 362.330 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 362.330 Td /F1 9.8 Tf [(Cepeda C, Cummings DM, Andre VM, Holley SM, Levine MS \(2010\) Genetic mouse models of Huntington's disease: focus )] TJ ET BT 26.250 350.425 Td /F1 9.8 Tf [(on electrophysiological mechanisms. ASN Neuro 2:e00033.)] TJ ET BT 26.250 331.020 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 331.020 Td /F1 9.8 Tf [(Klapstein GJ, Fisher RS, Zanjani H, Cepeda C, Jokel ES, Chesselet MF, Levine MS \(2001\) Electrophysiological and )] TJ ET BT 26.250 319.116 Td /F1 9.8 Tf [(Morphological Changes in Striatal Spiny Neurons in R6/2 Huntington's Disease Transgenic Mice. J Neurophysiol 86:2667-2677.)] TJ ET BT 26.250 299.711 Td /F1 9.8 Tf [(9.)] TJ ET BT 38.132 299.711 Td /F1 9.8 Tf [(Cepeda C, Hurst RS, Calvert CR, Hernandez-Echeagaray E, Nguyen OK, Jocoy E, Christian LJ, Ariano MA, Levine MS )] TJ ET BT 26.250 287.806 Td /F1 9.8 Tf [(\(2003\) Transient and progressive electrophysiological alterations in the corticostriatal pathway in a mouse model of Huntington's )] TJ ET BT 26.250 275.901 Td /F1 9.8 Tf [(disease. J Neurosci 23:961-969.)] TJ ET BT 26.250 256.497 Td /F1 9.8 Tf [(10.)] TJ ET BT 43.553 256.497 Td /F1 9.8 Tf [(Joshi PR, Wu NP, Andre VM, Cummings DM, Cepeda C, Joyce JA, Carroll JB, Leavitt BR, Hayden MR, Levine MS, )] TJ ET BT 26.250 244.592 Td /F1 9.8 Tf [(Bamford NS \(2009\) Age-dependent alterations of corticostriatal activity in the YAC128 mouse model of Huntington disease. J )] TJ ET BT 26.250 232.687 Td /F1 9.8 Tf [(Neurosci 29:2414-2427.)] TJ ET BT 26.250 213.282 Td /F1 9.8 Tf [(11.)] TJ ET BT 43.553 213.282 Td /F1 9.8 Tf [(Cummings DM, Andre VM, Uzgil BO, Gee SM, Fisher YE, Cepeda C, Levine MS \(2009\) Alterations in cortical excitation and )] TJ ET BT 26.250 201.378 Td /F1 9.8 Tf [(inhibition in genetic mouse models of Huntington's disease. J Neurosci 29:10371-10386.)] TJ ET BT 26.250 181.973 Td /F1 9.8 Tf [(12.)] TJ ET BT 43.553 181.973 Td /F1 9.8 Tf [(Pallier PN, Maywood ES, Zheng Z, Chesham JE, Inyushkin AN, Dyball R, Hastings MH, Morton AJ \(2007\) Pharmacological )] TJ ET BT 26.250 170.068 Td /F1 9.8 Tf [(imposition of sleep slows cognitive decline and reverses dysregulation of circadian gene expression in a transgenic mouse )] TJ ET BT 26.250 158.163 Td /F1 9.8 Tf [(model of Huntington's disease. J Neurosci 27:7869-7878.)] TJ ET BT 26.250 138.759 Td /F1 9.8 Tf [(13.)] TJ ET BT 43.553 138.759 Td /F1 9.8 Tf [(Masuda N, Peng Q, Li Q, Jiang M, Liang Y, Wang X, Zhao M, Wang W, Ross CA, Duan W \(2008\) Tiagabine is )] TJ ET BT 26.250 126.854 Td /F1 9.8 Tf [(neuroprotective in the N171-82Q and R6/2 mouse models of Huntington's disease. Neurobiol Dis 30:293-302.)] TJ ET BT 26.250 107.449 Td /F1 9.8 Tf [(14.)] TJ ET BT 43.553 107.449 Td /F1 9.8 Tf [(Stack EC, Dedeoglu A, Smith KM, Cormier K, Kubilus JK, Bogdanov M, Matson WR,Yang L, Jenkins BG, Luthi-Carter R, )] TJ ET BT 26.250 95.544 Td /F1 9.8 Tf [(Kowall NW, Hersch SM, Beal MF, Ferrante RJ \(2007\) Neuroprotective effects of synaptic modulation in Huntington's disease )] TJ ET BT 26.250 83.640 Td /F1 9.8 Tf [(R6/2 mice. J Neurosci 27:12908-12915.)] TJ ET BT 26.250 64.235 Td /F1 9.8 Tf [(15.)] TJ ET BT 43.553 64.235 Td /F1 9.8 Tf [(Levine MS, Klapstein GJ, Koppel A, Gruen E, Cepeda C, Vargas ME, Jokel ES, Carpenter EM, Zanjani H, Hurst RS, )] TJ ET BT 26.250 52.330 Td /F1 9.8 Tf [(Efstratiadis A, Zeitlin S, Chesselet MF \(1999\) Enhanced sensitivity to N-methyl-D-aspartate receptor activation in transgenic and )] TJ ET Q q 15.000 38.045 577.500 738.955 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(progressive disconnection between cortex and striatum, which may be responsible for late HD symptoms. Each manipulation )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(had different success rates depending on the disease stage, suggesting that careful monitoring of patient disease stage is )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(necessary for design of treatment regimens. In addition, our data suggest that both physical activity and polypharmacy may be )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(indicated in order to slow the progression of HD. All of these treatments ameliorated or reversed the electrophysiological )] TJ ET BT 26.250 719.857 Td /F1 9.8 Tf [(abnormalities. However, further research is required to reduce potential negative side effects of these agents.)] TJ ET BT 26.250 683.255 Td /F4 12.0 Tf [(Competing Interests)] TJ ET BT 26.250 663.300 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 626.698 Td /F4 12.0 Tf [(Acknowledgements)] TJ ET BT 26.250 606.744 Td /F1 9.8 Tf [(We would like to acknowledge Irene Yamazaki, Nanping Wu, Joshua L. Plotkin, Behnoud Beroukhim and Xiaoping Sun for their )] TJ ET BT 26.250 594.839 Td /F1 9.8 Tf [(help in data gathering and analysis. We also thank Donna Crandall for her help with the figures.)] TJ ET BT 26.250 565.736 Td /F4 12.0 Tf [(References)] TJ ET BT 26.250 538.282 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 538.282 Td /F1 9.8 Tf [(The Huntington's Disease Collaborative Research Group \(1993\) A novel gene containing a trinucleotide repeat that is )] TJ ET BT 26.250 526.377 Td /F1 9.8 Tf [(expanded and unstable on Huntington's disease chromosomes. Cell 72:971-983.)] TJ ET BT 26.250 506.973 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 506.973 Td /F1 9.8 Tf [(Vonsattel JP, DiFiglia M \(1998\) Huntington disease. J Neuropathol Exp Neurol 57:369-384.)] TJ ET BT 26.250 487.568 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 487.568 Td /F1 9.8 Tf [(Bates G, Harper PS, Jones L \(2002\) Huntington's disease, 3rd Edition. Oxford ; New York: Oxford University Press.)] TJ ET BT 26.250 468.163 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 468.163 Td /F1 9.8 Tf [(Levine MS, Cepeda C, Hickey MA, Fleming SM, Chesselet MF \(2004\) Genetic mouse models of Huntington's and )] TJ ET BT 26.250 456.258 Td /F1 9.8 Tf [(Parkinson's diseases: illuminating but imperfect. Trends Neurosci 27:691-697.)] TJ ET BT 26.250 436.854 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 436.854 Td /F1 9.8 Tf [(Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW, )] TJ ET BT 26.250 424.949 Td /F1 9.8 Tf [(Bates GP \(1996\) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological )] TJ ET BT 26.250 413.044 Td /F1 9.8 Tf [(phenotype in transgenic mice. Cell 87:493-506.)] TJ ET BT 26.250 393.639 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 393.639 Td /F1 9.8 Tf [(Cepeda C, Wu N, Andr VM, Cummings DM, Levine MS \(2007\) The corticostriatal pathway in Huntington's disease. Prog )] TJ ET BT 26.250 381.735 Td /F1 9.8 Tf [(Neuorbiol 81:253-271.)] TJ ET BT 26.250 362.330 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 362.330 Td /F1 9.8 Tf [(Cepeda C, Cummings DM, Andre VM, Holley SM, Levine MS \(2010\) Genetic mouse models of Huntington's disease: focus )] TJ ET BT 26.250 350.425 Td /F1 9.8 Tf [(on electrophysiological mechanisms. ASN Neuro 2:e00033.)] TJ ET BT 26.250 331.020 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 331.020 Td /F1 9.8 Tf [(Klapstein GJ, Fisher RS, Zanjani H, Cepeda C, Jokel ES, Chesselet MF, Levine MS \(2001\) Electrophysiological and )] TJ ET BT 26.250 319.116 Td /F1 9.8 Tf [(Morphological Changes in Striatal Spiny Neurons in R6/2 Huntington's Disease Transgenic Mice. J Neurophysiol 86:2667-2677.)] TJ ET BT 26.250 299.711 Td /F1 9.8 Tf [(9.)] TJ ET BT 38.132 299.711 Td /F1 9.8 Tf [(Cepeda C, Hurst RS, Calvert CR, Hernandez-Echeagaray E, Nguyen OK, Jocoy E, Christian LJ, Ariano MA, Levine MS )] TJ ET BT 26.250 287.806 Td /F1 9.8 Tf [(\(2003\) Transient and progressive electrophysiological alterations in the corticostriatal pathway in a mouse model of Huntington's )] TJ ET BT 26.250 275.901 Td /F1 9.8 Tf [(disease. J Neurosci 23:961-969.)] TJ ET BT 26.250 256.497 Td /F1 9.8 Tf [(10.)] TJ ET BT 43.553 256.497 Td /F1 9.8 Tf [(Joshi PR, Wu NP, Andre VM, Cummings DM, Cepeda C, Joyce JA, Carroll JB, Leavitt BR, Hayden MR, Levine MS, )] TJ ET BT 26.250 244.592 Td /F1 9.8 Tf [(Bamford NS \(2009\) Age-dependent alterations of corticostriatal activity in the YAC128 mouse model of Huntington disease. J )] TJ ET BT 26.250 232.687 Td /F1 9.8 Tf [(Neurosci 29:2414-2427.)] TJ ET BT 26.250 213.282 Td /F1 9.8 Tf [(11.)] TJ ET BT 43.553 213.282 Td /F1 9.8 Tf [(Cummings DM, Andre VM, Uzgil BO, Gee SM, Fisher YE, Cepeda C, Levine MS \(2009\) Alterations in cortical excitation and )] TJ ET BT 26.250 201.378 Td /F1 9.8 Tf [(inhibition in genetic mouse models of Huntington's disease. J Neurosci 29:10371-10386.)] TJ ET BT 26.250 181.973 Td /F1 9.8 Tf [(12.)] TJ ET BT 43.553 181.973 Td /F1 9.8 Tf [(Pallier PN, Maywood ES, Zheng Z, Chesham JE, Inyushkin AN, Dyball R, Hastings MH, Morton AJ \(2007\) Pharmacological )] TJ ET BT 26.250 170.068 Td /F1 9.8 Tf [(imposition of sleep slows cognitive decline and reverses dysregulation of circadian gene expression in a transgenic mouse )] TJ ET BT 26.250 158.163 Td /F1 9.8 Tf [(model of Huntington's disease. J Neurosci 27:7869-7878.)] TJ ET BT 26.250 138.759 Td /F1 9.8 Tf [(13.)] TJ ET BT 43.553 138.759 Td /F1 9.8 Tf [(Masuda N, Peng Q, Li Q, Jiang M, Liang Y, Wang X, Zhao M, Wang W, Ross CA, Duan W \(2008\) Tiagabine is )] TJ ET BT 26.250 126.854 Td /F1 9.8 Tf [(neuroprotective in the N171-82Q and R6/2 mouse models of Huntington's disease. Neurobiol Dis 30:293-302.)] TJ ET BT 26.250 107.449 Td /F1 9.8 Tf [(14.)] TJ ET BT 43.553 107.449 Td /F1 9.8 Tf [(Stack EC, Dedeoglu A, Smith KM, Cormier K, Kubilus JK, Bogdanov M, Matson WR,Yang L, Jenkins BG, Luthi-Carter R, )] TJ ET BT 26.250 95.544 Td /F1 9.8 Tf [(Kowall NW, Hersch SM, Beal MF, Ferrante RJ \(2007\) Neuroprotective effects of synaptic modulation in Huntington's disease )] TJ ET BT 26.250 83.640 Td /F1 9.8 Tf [(R6/2 mice. J Neurosci 27:12908-12915.)] TJ ET BT 26.250 64.235 Td /F1 9.8 Tf [(15.)] TJ ET BT 43.553 64.235 Td /F1 9.8 Tf [(Levine MS, Klapstein GJ, Koppel A, Gruen E, Cepeda C, Vargas ME, Jokel ES, Carpenter EM, Zanjani H, Hurst RS, )] TJ ET BT 26.250 52.330 Td /F1 9.8 Tf [(Efstratiadis A, Zeitlin S, Chesselet MF \(1999\) Enhanced sensitivity to N-methyl-D-aspartate receptor activation in transgenic and )] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(10)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 519 0 obj << /Type /Page /Parent 3 0 R /Contents 520 0 R >> endobj 520 0 obj << /Length 22232 >> stream 0.271 0.267 0.267 rg q 15.000 48.072 577.500 728.928 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(knockin mouse models of Huntington's disease. J Neurosci Res 58:515-532.)] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(16.)] TJ ET BT 43.553 748.071 Td /F1 9.8 Tf [(Cepeda C, Ariano MA, Calvert CR, Flores-Hernandez J, Chandler SH, Leavitt BR, Hayden MR, Levine MS \(2001\) NMDA )] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(receptor function in mouse models of Huntington disease. J Neurosci Res 66:525-539.)] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(17.)] TJ ET BT 43.553 716.762 Td /F1 9.8 Tf [(Okamoto S, Pouladi MA, Talantova M, Yao D, Xia P, Ehrnhoefer DE, Zaidi R, Clemente A, Kaul M, Graham RK, Zhang D, )] TJ ET BT 26.250 704.857 Td /F1 9.8 Tf [(Vincent Chen HS, Tong G, Hayden MR, Lipton SA \(2009\) Balance between synaptic versus extrasynaptic NMDA receptor )] TJ ET BT 26.250 692.952 Td /F1 9.8 Tf [(activity influences inclusions and neurotoxicity of mutant huntingtin. Nat Med 15:1407-1413.)] TJ ET BT 26.250 673.548 Td /F1 9.8 Tf [(18.)] TJ ET BT 43.553 673.548 Td /F1 9.8 Tf [(Milnerwood AJ, Gladding CM, Pouladi MA, Kaufman AM, Hines RM, Boyd JD, Ko RW, Vasuta OC, Graham RK, Hayden )] TJ ET BT 26.250 661.643 Td /F1 9.8 Tf [(MR, Murphy TH, Raymond LA \(2010\) Early increase in extrasynaptic NMDA receptor signaling and expression contributes to )] TJ ET BT 26.250 649.738 Td /F1 9.8 Tf [(phenotype onset in Huntington's disease mice. Neuron 65:178-190.)] TJ ET BT 26.250 630.333 Td /F1 9.8 Tf [(19.)] TJ ET BT 43.553 630.333 Td /F1 9.8 Tf [(Smith AD, Zigmond MJ \(2003\) Can the brain be protected through exercise? Lessons from an animal model of )] TJ ET BT 26.250 618.429 Td /F1 9.8 Tf [(parkinsonism. Exp Neurol 184:31-39.)] TJ ET BT 26.250 599.024 Td /F1 9.8 Tf [(20.)] TJ ET BT 43.553 599.024 Td /F1 9.8 Tf [(Cotman CW, Berchtold NC \(2002\) Exercise: a behavioral intervention to enhance brain health and plasticity. Trends )] TJ ET BT 26.250 587.119 Td /F1 9.8 Tf [(Neurosci 25:295-301.)] TJ ET BT 26.250 567.714 Td /F1 9.8 Tf [(21.)] TJ ET BT 43.553 567.714 Td /F1 9.8 Tf [(Siegenthaler MM, Berchtold NC, Cotman CW, Keirstead HS \(2008\) Voluntary running attenuates age-related deficits )] TJ ET BT 26.250 555.810 Td /F1 9.8 Tf [(following SCI. Exp Neurol 210:207-216.)] TJ ET BT 26.250 536.405 Td /F1 9.8 Tf [(22.)] TJ ET BT 43.553 536.405 Td /F1 9.8 Tf [(van Praag H \(2008\) Neurogenesis and exercise: past and future directions. Neuromolecular Med 10:128-140.)] TJ ET BT 26.250 517.000 Td /F1 9.8 Tf [(23.)] TJ ET BT 43.553 517.000 Td /F1 9.8 Tf [(van Dellen A, Blakemore C, Deacon R, York D, Hannan AJ \(2000\) Delaying the onset of Huntington's in mice. Nature )] TJ ET BT 26.250 505.095 Td /F1 9.8 Tf [(404:721-722.)] TJ ET BT 26.250 485.691 Td /F1 9.8 Tf [(24.)] TJ ET BT 43.553 485.691 Td /F1 9.8 Tf [(Kase H, Aoyama S, Ichimura M, Ikeda K, Ishii A, Kanda T, Koga K, Koike N, Kurokawa M, Kuwana Y, Mori A, Nakamura J, )] TJ ET BT 26.250 473.786 Td /F1 9.8 Tf [(Nonaka H, Ochi M, Saki M, Shimada J, Shindou T, Shiozaki S, Suzuki F, Takeda M, Yanagawa K, Richardson PJ, Jenner P, )] TJ ET BT 26.250 461.881 Td /F1 9.8 Tf [(Bedard P, Borrelli E, Hauser RA, Chase TN \(2003\) Progress in pursuit of therapeutic A2A antagonists: the adenosine A2A )] TJ ET BT 26.250 449.976 Td /F1 9.8 Tf [(receptor selective antagonist KW6002: research and development toward a novel nondopaminergic therapy for Parkinson's )] TJ ET BT 26.250 438.072 Td /F1 9.8 Tf [(disease. Neurology 61:S97-100.)] TJ ET BT 26.250 418.667 Td /F1 9.8 Tf [(25.)] TJ ET BT 43.553 418.667 Td /F1 9.8 Tf [(Pinna A \(2009\) Novel investigational adenosine A2A receptor antagonists for Parkinson's disease. Expert Opin Investig )] TJ ET BT 26.250 406.762 Td /F1 9.8 Tf [(Drugs 18:1619-1631.)] TJ ET BT 26.250 387.357 Td /F1 9.8 Tf [(26.)] TJ ET BT 43.553 387.357 Td /F1 9.8 Tf [(Tarditi A, Camurri A, Varani K, Borea PA, Woodman B, Bates G, Cattaneo E, Abbracchio MP \(2006\) Early and transient )] TJ ET BT 26.250 375.453 Td /F1 9.8 Tf [(alteration of adenosine A2A receptor signaling in a mouse model of Huntington disease. Neurobiol Dis 23:44-53.)] TJ ET BT 26.250 356.048 Td /F1 9.8 Tf [(27.)] TJ ET BT 43.553 356.048 Td /F1 9.8 Tf [(Martire A, Calamandrei G, Felici F, Scattoni ML, Lastoria G, Domenici MR, Tebano MT, Popoli P \(2007\) Opposite effects of )] TJ ET BT 26.250 344.143 Td /F1 9.8 Tf [(the A2A receptor agonist CGS21680 in the striatum of Huntington's disease versus wild-type mice. Neurosci Lett 417:78-83.)] TJ ET BT 26.250 324.738 Td /F1 9.8 Tf [(28.)] TJ ET BT 43.553 324.738 Td /F1 9.8 Tf [(Chou SY, Lee YC, Chen HM, Chiang MC, Lai HL, Chang HH, Wu YC, Sun CN, Chien CL, Lin YS, Wang SC, Tung YY, )] TJ ET BT 26.250 312.834 Td /F1 9.8 Tf [(Chang C, Chern Y \(2005\) CGS21680 attenuates symptoms of Huntington's disease in a transgenic mouse model. J Neurochem )] TJ ET BT 26.250 300.929 Td /F1 9.8 Tf [(93:310-320.)] TJ ET BT 26.250 281.524 Td /F1 9.8 Tf [(29.)] TJ ET BT 43.553 281.524 Td /F1 9.8 Tf [(Domenici MR, Scattoni ML, Martire A, Lastoria G, Potenza RL, Borioni A, Venerosi A, Calamandrei G, Popoli P \(2007\) )] TJ ET BT 26.250 269.619 Td /F1 9.8 Tf [(Behavioral and electrophysiological effects of the adenosine A2A receptor antagonist SCH 58261 in R6/2 Huntington's disease )] TJ ET BT 26.250 257.715 Td /F1 9.8 Tf [(mice. Neurobiol Dis 28:197-205.)] TJ ET BT 26.250 238.310 Td /F1 9.8 Tf [(30.)] TJ ET BT 43.553 238.310 Td /F1 9.8 Tf [(Jin R, Clark S, Weeks AM, Dudman JT, Gouaux E, Partin KM \(2005\) Mechanism of positive allosteric modulators acting on )] TJ ET BT 26.250 226.405 Td /F1 9.8 Tf [(AMPA receptors. J Neurosci 25:9027-9036.)] TJ ET BT 26.250 207.000 Td /F1 9.8 Tf [(31.)] TJ ET BT 43.553 207.000 Td /F1 9.8 Tf [(Lynch G \(2006\) Glutamate-based therapeutic approaches: ampakines. Curr Opin Pharmacol 6:82-88.)] TJ ET BT 26.250 187.596 Td /F1 9.8 Tf [(32.)] TJ ET BT 43.553 187.596 Td /F1 9.8 Tf [(Lauterborn JC, Truong GS, Baudry M, Bi X, Lynch G, Gall CM \(2003\) Chronic elevation of brain-derived neurotrophic factor )] TJ ET BT 26.250 175.691 Td /F1 9.8 Tf [(by ampakines. J Pharmacol Exp Ther 307:297-305.)] TJ ET BT 26.250 156.286 Td /F1 9.8 Tf [(33.)] TJ ET BT 43.553 156.286 Td /F1 9.8 Tf [(Simmons DA, Rex CS, Palmer L, Pandyarajan V, Fedulov V, Gall CM, Lynch G \(2009\) Up-regulating BDNF with an )] TJ ET BT 26.250 144.381 Td /F1 9.8 Tf [(ampakine rescues synaptic plasticity and memory in Huntington's disease knockin mice. Proc Natl Acad Sci U S A 106:4906-)] TJ ET BT 26.250 132.477 Td /F1 9.8 Tf [(4911.)] TJ ET BT 26.250 113.072 Td /F1 9.8 Tf [(34.)] TJ ET BT 43.553 113.072 Td /F1 9.8 Tf [(Hickey MA, Gallant K, Gross GG, Levine MS, Chesselet MF \(2005\) Early behavioral deficits in R6/2 mice suitable for use in )] TJ ET BT 26.250 101.167 Td /F1 9.8 Tf [(preclinical drug testing. Neurobiol Dis 20:1-11.)] TJ ET BT 26.250 81.762 Td /F1 9.8 Tf [(35.)] TJ ET BT 43.553 81.762 Td /F1 9.8 Tf [(Hickey MA, Kosmalska A, Enayati J, Cohen R, Zeitlin S, Levine MS, Chesselet MF \(2008\) Extensive early motor and non-)] TJ ET BT 26.250 69.858 Td /F1 9.8 Tf [(motor behavioral deficits are followed by striatal neuronal loss in knock-in Huntington's disease mice. Neuroscience 157:280-)] TJ ET BT 26.250 57.953 Td /F1 9.8 Tf [(295.)] TJ ET Q q 15.000 48.072 577.500 728.928 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(knockin mouse models of Huntington's disease. J Neurosci Res 58:515-532.)] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(16.)] TJ ET BT 43.553 748.071 Td /F1 9.8 Tf [(Cepeda C, Ariano MA, Calvert CR, Flores-Hernandez J, Chandler SH, Leavitt BR, Hayden MR, Levine MS \(2001\) NMDA )] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(receptor function in mouse models of Huntington disease. J Neurosci Res 66:525-539.)] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(17.)] TJ ET BT 43.553 716.762 Td /F1 9.8 Tf [(Okamoto S, Pouladi MA, Talantova M, Yao D, Xia P, Ehrnhoefer DE, Zaidi R, Clemente A, Kaul M, Graham RK, Zhang D, )] TJ ET BT 26.250 704.857 Td /F1 9.8 Tf [(Vincent Chen HS, Tong G, Hayden MR, Lipton SA \(2009\) Balance between synaptic versus extrasynaptic NMDA receptor )] TJ ET BT 26.250 692.952 Td /F1 9.8 Tf [(activity influences inclusions and neurotoxicity of mutant huntingtin. Nat Med 15:1407-1413.)] TJ ET BT 26.250 673.548 Td /F1 9.8 Tf [(18.)] TJ ET BT 43.553 673.548 Td /F1 9.8 Tf [(Milnerwood AJ, Gladding CM, Pouladi MA, Kaufman AM, Hines RM, Boyd JD, Ko RW, Vasuta OC, Graham RK, Hayden )] TJ ET BT 26.250 661.643 Td /F1 9.8 Tf [(MR, Murphy TH, Raymond LA \(2010\) Early increase in extrasynaptic NMDA receptor signaling and expression contributes to )] TJ ET BT 26.250 649.738 Td /F1 9.8 Tf [(phenotype onset in Huntington's disease mice. Neuron 65:178-190.)] TJ ET BT 26.250 630.333 Td /F1 9.8 Tf [(19.)] TJ ET BT 43.553 630.333 Td /F1 9.8 Tf [(Smith AD, Zigmond MJ \(2003\) Can the brain be protected through exercise? Lessons from an animal model of )] TJ ET BT 26.250 618.429 Td /F1 9.8 Tf [(parkinsonism. Exp Neurol 184:31-39.)] TJ ET BT 26.250 599.024 Td /F1 9.8 Tf [(20.)] TJ ET BT 43.553 599.024 Td /F1 9.8 Tf [(Cotman CW, Berchtold NC \(2002\) Exercise: a behavioral intervention to enhance brain health and plasticity. Trends )] TJ ET BT 26.250 587.119 Td /F1 9.8 Tf [(Neurosci 25:295-301.)] TJ ET BT 26.250 567.714 Td /F1 9.8 Tf [(21.)] TJ ET BT 43.553 567.714 Td /F1 9.8 Tf [(Siegenthaler MM, Berchtold NC, Cotman CW, Keirstead HS \(2008\) Voluntary running attenuates age-related deficits )] TJ ET BT 26.250 555.810 Td /F1 9.8 Tf [(following SCI. Exp Neurol 210:207-216.)] TJ ET BT 26.250 536.405 Td /F1 9.8 Tf [(22.)] TJ ET BT 43.553 536.405 Td /F1 9.8 Tf [(van Praag H \(2008\) Neurogenesis and exercise: past and future directions. Neuromolecular Med 10:128-140.)] TJ ET BT 26.250 517.000 Td /F1 9.8 Tf [(23.)] TJ ET BT 43.553 517.000 Td /F1 9.8 Tf [(van Dellen A, Blakemore C, Deacon R, York D, Hannan AJ \(2000\) Delaying the onset of Huntington's in mice. Nature )] TJ ET BT 26.250 505.095 Td /F1 9.8 Tf [(404:721-722.)] TJ ET BT 26.250 485.691 Td /F1 9.8 Tf [(24.)] TJ ET BT 43.553 485.691 Td /F1 9.8 Tf [(Kase H, Aoyama S, Ichimura M, Ikeda K, Ishii A, Kanda T, Koga K, Koike N, Kurokawa M, Kuwana Y, Mori A, Nakamura J, )] TJ ET BT 26.250 473.786 Td /F1 9.8 Tf [(Nonaka H, Ochi M, Saki M, Shimada J, Shindou T, Shiozaki S, Suzuki F, Takeda M, Yanagawa K, Richardson PJ, Jenner P, )] TJ ET BT 26.250 461.881 Td /F1 9.8 Tf [(Bedard P, Borrelli E, Hauser RA, Chase TN \(2003\) Progress in pursuit of therapeutic A2A antagonists: the adenosine A2A )] TJ ET BT 26.250 449.976 Td /F1 9.8 Tf [(receptor selective antagonist KW6002: research and development toward a novel nondopaminergic therapy for Parkinson's )] TJ ET BT 26.250 438.072 Td /F1 9.8 Tf [(disease. Neurology 61:S97-100.)] TJ ET BT 26.250 418.667 Td /F1 9.8 Tf [(25.)] TJ ET BT 43.553 418.667 Td /F1 9.8 Tf [(Pinna A \(2009\) Novel investigational adenosine A2A receptor antagonists for Parkinson's disease. Expert Opin Investig )] TJ ET BT 26.250 406.762 Td /F1 9.8 Tf [(Drugs 18:1619-1631.)] TJ ET BT 26.250 387.357 Td /F1 9.8 Tf [(26.)] TJ ET BT 43.553 387.357 Td /F1 9.8 Tf [(Tarditi A, Camurri A, Varani K, Borea PA, Woodman B, Bates G, Cattaneo E, Abbracchio MP \(2006\) Early and transient )] TJ ET BT 26.250 375.453 Td /F1 9.8 Tf [(alteration of adenosine A2A receptor signaling in a mouse model of Huntington disease. Neurobiol Dis 23:44-53.)] TJ ET BT 26.250 356.048 Td /F1 9.8 Tf [(27.)] TJ ET BT 43.553 356.048 Td /F1 9.8 Tf [(Martire A, Calamandrei G, Felici F, Scattoni ML, Lastoria G, Domenici MR, Tebano MT, Popoli P \(2007\) Opposite effects of )] TJ ET BT 26.250 344.143 Td /F1 9.8 Tf [(the A2A receptor agonist CGS21680 in the striatum of Huntington's disease versus wild-type mice. Neurosci Lett 417:78-83.)] TJ ET BT 26.250 324.738 Td /F1 9.8 Tf [(28.)] TJ ET BT 43.553 324.738 Td /F1 9.8 Tf [(Chou SY, Lee YC, Chen HM, Chiang MC, Lai HL, Chang HH, Wu YC, Sun CN, Chien CL, Lin YS, Wang SC, Tung YY, )] TJ ET BT 26.250 312.834 Td /F1 9.8 Tf [(Chang C, Chern Y \(2005\) CGS21680 attenuates symptoms of Huntington's disease in a transgenic mouse model. J Neurochem )] TJ ET BT 26.250 300.929 Td /F1 9.8 Tf [(93:310-320.)] TJ ET BT 26.250 281.524 Td /F1 9.8 Tf [(29.)] TJ ET BT 43.553 281.524 Td /F1 9.8 Tf [(Domenici MR, Scattoni ML, Martire A, Lastoria G, Potenza RL, Borioni A, Venerosi A, Calamandrei G, Popoli P \(2007\) )] TJ ET BT 26.250 269.619 Td /F1 9.8 Tf [(Behavioral and electrophysiological effects of the adenosine A2A receptor antagonist SCH 58261 in R6/2 Huntington's disease )] TJ ET BT 26.250 257.715 Td /F1 9.8 Tf [(mice. Neurobiol Dis 28:197-205.)] TJ ET BT 26.250 238.310 Td /F1 9.8 Tf [(30.)] TJ ET BT 43.553 238.310 Td /F1 9.8 Tf [(Jin R, Clark S, Weeks AM, Dudman JT, Gouaux E, Partin KM \(2005\) Mechanism of positive allosteric modulators acting on )] TJ ET BT 26.250 226.405 Td /F1 9.8 Tf [(AMPA receptors. J Neurosci 25:9027-9036.)] TJ ET BT 26.250 207.000 Td /F1 9.8 Tf [(31.)] TJ ET BT 43.553 207.000 Td /F1 9.8 Tf [(Lynch G \(2006\) Glutamate-based therapeutic approaches: ampakines. Curr Opin Pharmacol 6:82-88.)] TJ ET BT 26.250 187.596 Td /F1 9.8 Tf [(32.)] TJ ET BT 43.553 187.596 Td /F1 9.8 Tf [(Lauterborn JC, Truong GS, Baudry M, Bi X, Lynch G, Gall CM \(2003\) Chronic elevation of brain-derived neurotrophic factor )] TJ ET BT 26.250 175.691 Td /F1 9.8 Tf [(by ampakines. J Pharmacol Exp Ther 307:297-305.)] TJ ET BT 26.250 156.286 Td /F1 9.8 Tf [(33.)] TJ ET BT 43.553 156.286 Td /F1 9.8 Tf [(Simmons DA, Rex CS, Palmer L, Pandyarajan V, Fedulov V, Gall CM, Lynch G \(2009\) Up-regulating BDNF with an )] TJ ET BT 26.250 144.381 Td /F1 9.8 Tf [(ampakine rescues synaptic plasticity and memory in Huntington's disease knockin mice. Proc Natl Acad Sci U S A 106:4906-)] TJ ET BT 26.250 132.477 Td /F1 9.8 Tf [(4911.)] TJ ET BT 26.250 113.072 Td /F1 9.8 Tf [(34.)] TJ ET BT 43.553 113.072 Td /F1 9.8 Tf [(Hickey MA, Gallant K, Gross GG, Levine MS, Chesselet MF \(2005\) Early behavioral deficits in R6/2 mice suitable for use in )] TJ ET BT 26.250 101.167 Td /F1 9.8 Tf [(preclinical drug testing. Neurobiol Dis 20:1-11.)] TJ ET BT 26.250 81.762 Td /F1 9.8 Tf [(35.)] TJ ET BT 43.553 81.762 Td /F1 9.8 Tf [(Hickey MA, Kosmalska A, Enayati J, Cohen R, Zeitlin S, Levine MS, Chesselet MF \(2008\) Extensive early motor and non-)] TJ ET BT 26.250 69.858 Td /F1 9.8 Tf [(motor behavioral deficits are followed by striatal neuronal loss in knock-in Huntington's disease mice. Neuroscience 157:280-)] TJ ET BT 26.250 57.953 Td /F1 9.8 Tf [(295.)] TJ ET Q q 15.000 48.072 577.500 728.928 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(knockin mouse models of Huntington's disease. J Neurosci Res 58:515-532.)] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(16.)] TJ ET BT 43.553 748.071 Td /F1 9.8 Tf [(Cepeda C, Ariano MA, Calvert CR, Flores-Hernandez J, Chandler SH, Leavitt BR, Hayden MR, Levine MS \(2001\) NMDA )] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(receptor function in mouse models of Huntington disease. J Neurosci Res 66:525-539.)] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(17.)] TJ ET BT 43.553 716.762 Td /F1 9.8 Tf [(Okamoto S, Pouladi MA, Talantova M, Yao D, Xia P, Ehrnhoefer DE, Zaidi R, Clemente A, Kaul M, Graham RK, Zhang D, )] TJ ET BT 26.250 704.857 Td /F1 9.8 Tf [(Vincent Chen HS, Tong G, Hayden MR, Lipton SA \(2009\) Balance between synaptic versus extrasynaptic NMDA receptor )] TJ ET BT 26.250 692.952 Td /F1 9.8 Tf [(activity influences inclusions and neurotoxicity of mutant huntingtin. Nat Med 15:1407-1413.)] TJ ET BT 26.250 673.548 Td /F1 9.8 Tf [(18.)] TJ ET BT 43.553 673.548 Td /F1 9.8 Tf [(Milnerwood AJ, Gladding CM, Pouladi MA, Kaufman AM, Hines RM, Boyd JD, Ko RW, Vasuta OC, Graham RK, Hayden )] TJ ET BT 26.250 661.643 Td /F1 9.8 Tf [(MR, Murphy TH, Raymond LA \(2010\) Early increase in extrasynaptic NMDA receptor signaling and expression contributes to )] TJ ET BT 26.250 649.738 Td /F1 9.8 Tf [(phenotype onset in Huntington's disease mice. Neuron 65:178-190.)] TJ ET BT 26.250 630.333 Td /F1 9.8 Tf [(19.)] TJ ET BT 43.553 630.333 Td /F1 9.8 Tf [(Smith AD, Zigmond MJ \(2003\) Can the brain be protected through exercise? Lessons from an animal model of )] TJ ET BT 26.250 618.429 Td /F1 9.8 Tf [(parkinsonism. Exp Neurol 184:31-39.)] TJ ET BT 26.250 599.024 Td /F1 9.8 Tf [(20.)] TJ ET BT 43.553 599.024 Td /F1 9.8 Tf [(Cotman CW, Berchtold NC \(2002\) Exercise: a behavioral intervention to enhance brain health and plasticity. Trends )] TJ ET BT 26.250 587.119 Td /F1 9.8 Tf [(Neurosci 25:295-301.)] TJ ET BT 26.250 567.714 Td /F1 9.8 Tf [(21.)] TJ ET BT 43.553 567.714 Td /F1 9.8 Tf [(Siegenthaler MM, Berchtold NC, Cotman CW, Keirstead HS \(2008\) Voluntary running attenuates age-related deficits )] TJ ET BT 26.250 555.810 Td /F1 9.8 Tf [(following SCI. Exp Neurol 210:207-216.)] TJ ET BT 26.250 536.405 Td /F1 9.8 Tf [(22.)] TJ ET BT 43.553 536.405 Td /F1 9.8 Tf [(van Praag H \(2008\) Neurogenesis and exercise: past and future directions. Neuromolecular Med 10:128-140.)] TJ ET BT 26.250 517.000 Td /F1 9.8 Tf [(23.)] TJ ET BT 43.553 517.000 Td /F1 9.8 Tf [(van Dellen A, Blakemore C, Deacon R, York D, Hannan AJ \(2000\) Delaying the onset of Huntington's in mice. Nature )] TJ ET BT 26.250 505.095 Td /F1 9.8 Tf [(404:721-722.)] TJ ET BT 26.250 485.691 Td /F1 9.8 Tf [(24.)] TJ ET BT 43.553 485.691 Td /F1 9.8 Tf [(Kase H, Aoyama S, Ichimura M, Ikeda K, Ishii A, Kanda T, Koga K, Koike N, Kurokawa M, Kuwana Y, Mori A, Nakamura J, )] TJ ET BT 26.250 473.786 Td /F1 9.8 Tf [(Nonaka H, Ochi M, Saki M, Shimada J, Shindou T, Shiozaki S, Suzuki F, Takeda M, Yanagawa K, Richardson PJ, Jenner P, )] TJ ET BT 26.250 461.881 Td /F1 9.8 Tf [(Bedard P, Borrelli E, Hauser RA, Chase TN \(2003\) Progress in pursuit of therapeutic A2A antagonists: the adenosine A2A )] TJ ET BT 26.250 449.976 Td /F1 9.8 Tf [(receptor selective antagonist KW6002: research and development toward a novel nondopaminergic therapy for Parkinson's )] TJ ET BT 26.250 438.072 Td /F1 9.8 Tf [(disease. Neurology 61:S97-100.)] TJ ET BT 26.250 418.667 Td /F1 9.8 Tf [(25.)] TJ ET BT 43.553 418.667 Td /F1 9.8 Tf [(Pinna A \(2009\) Novel investigational adenosine A2A receptor antagonists for Parkinson's disease. Expert Opin Investig )] TJ ET BT 26.250 406.762 Td /F1 9.8 Tf [(Drugs 18:1619-1631.)] TJ ET BT 26.250 387.357 Td /F1 9.8 Tf [(26.)] TJ ET BT 43.553 387.357 Td /F1 9.8 Tf [(Tarditi A, Camurri A, Varani K, Borea PA, Woodman B, Bates G, Cattaneo E, Abbracchio MP \(2006\) Early and transient )] TJ ET BT 26.250 375.453 Td /F1 9.8 Tf [(alteration of adenosine A2A receptor signaling in a mouse model of Huntington disease. Neurobiol Dis 23:44-53.)] TJ ET BT 26.250 356.048 Td /F1 9.8 Tf [(27.)] TJ ET BT 43.553 356.048 Td /F1 9.8 Tf [(Martire A, Calamandrei G, Felici F, Scattoni ML, Lastoria G, Domenici MR, Tebano MT, Popoli P \(2007\) Opposite effects of )] TJ ET BT 26.250 344.143 Td /F1 9.8 Tf [(the A2A receptor agonist CGS21680 in the striatum of Huntington's disease versus wild-type mice. Neurosci Lett 417:78-83.)] TJ ET BT 26.250 324.738 Td /F1 9.8 Tf [(28.)] TJ ET BT 43.553 324.738 Td /F1 9.8 Tf [(Chou SY, Lee YC, Chen HM, Chiang MC, Lai HL, Chang HH, Wu YC, Sun CN, Chien CL, Lin YS, Wang SC, Tung YY, )] TJ ET BT 26.250 312.834 Td /F1 9.8 Tf [(Chang C, Chern Y \(2005\) CGS21680 attenuates symptoms of Huntington's disease in a transgenic mouse model. J Neurochem )] TJ ET BT 26.250 300.929 Td /F1 9.8 Tf [(93:310-320.)] TJ ET BT 26.250 281.524 Td /F1 9.8 Tf [(29.)] TJ ET BT 43.553 281.524 Td /F1 9.8 Tf [(Domenici MR, Scattoni ML, Martire A, Lastoria G, Potenza RL, Borioni A, Venerosi A, Calamandrei G, Popoli P \(2007\) )] TJ ET BT 26.250 269.619 Td /F1 9.8 Tf [(Behavioral and electrophysiological effects of the adenosine A2A receptor antagonist SCH 58261 in R6/2 Huntington's disease )] TJ ET BT 26.250 257.715 Td /F1 9.8 Tf [(mice. Neurobiol Dis 28:197-205.)] TJ ET BT 26.250 238.310 Td /F1 9.8 Tf [(30.)] TJ ET BT 43.553 238.310 Td /F1 9.8 Tf [(Jin R, Clark S, Weeks AM, Dudman JT, Gouaux E, Partin KM \(2005\) Mechanism of positive allosteric modulators acting on )] TJ ET BT 26.250 226.405 Td /F1 9.8 Tf [(AMPA receptors. J Neurosci 25:9027-9036.)] TJ ET BT 26.250 207.000 Td /F1 9.8 Tf [(31.)] TJ ET BT 43.553 207.000 Td /F1 9.8 Tf [(Lynch G \(2006\) Glutamate-based therapeutic approaches: ampakines. Curr Opin Pharmacol 6:82-88.)] TJ ET BT 26.250 187.596 Td /F1 9.8 Tf [(32.)] TJ ET BT 43.553 187.596 Td /F1 9.8 Tf [(Lauterborn JC, Truong GS, Baudry M, Bi X, Lynch G, Gall CM \(2003\) Chronic elevation of brain-derived neurotrophic factor )] TJ ET BT 26.250 175.691 Td /F1 9.8 Tf [(by ampakines. J Pharmacol Exp Ther 307:297-305.)] TJ ET BT 26.250 156.286 Td /F1 9.8 Tf [(33.)] TJ ET BT 43.553 156.286 Td /F1 9.8 Tf [(Simmons DA, Rex CS, Palmer L, Pandyarajan V, Fedulov V, Gall CM, Lynch G \(2009\) Up-regulating BDNF with an )] TJ ET BT 26.250 144.381 Td /F1 9.8 Tf [(ampakine rescues synaptic plasticity and memory in Huntington's disease knockin mice. Proc Natl Acad Sci U S A 106:4906-)] TJ ET BT 26.250 132.477 Td /F1 9.8 Tf [(4911.)] TJ ET BT 26.250 113.072 Td /F1 9.8 Tf [(34.)] TJ ET BT 43.553 113.072 Td /F1 9.8 Tf [(Hickey MA, Gallant K, Gross GG, Levine MS, Chesselet MF \(2005\) Early behavioral deficits in R6/2 mice suitable for use in )] TJ ET BT 26.250 101.167 Td /F1 9.8 Tf [(preclinical drug testing. Neurobiol Dis 20:1-11.)] TJ ET BT 26.250 81.762 Td /F1 9.8 Tf [(35.)] TJ ET BT 43.553 81.762 Td /F1 9.8 Tf [(Hickey MA, Kosmalska A, Enayati J, Cohen R, Zeitlin S, Levine MS, Chesselet MF \(2008\) Extensive early motor and non-)] TJ ET BT 26.250 69.858 Td /F1 9.8 Tf [(motor behavioral deficits are followed by striatal neuronal loss in knock-in Huntington's disease mice. Neuroscience 157:280-)] TJ ET BT 26.250 57.953 Td /F1 9.8 Tf [(295.)] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(11)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 521 0 obj << /Type /Page /Parent 3 0 R /Contents 522 0 R >> endobj 522 0 obj << /Length 13037 >> stream 0.271 0.267 0.267 rg q 15.000 358.072 577.500 418.928 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(36.)] TJ ET BT 43.553 759.976 Td /F1 9.8 Tf [(Watson JB, Hatami A, David H, Masliah E, Roberts K, Evans CE, Levine MS \(2009\) Alterations in corticostriatal synaptic )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(plasticity in mice overexpressing human alpha-synuclein. Neuroscience 159:501-513.)] TJ ET BT 26.250 728.667 Td /F1 9.8 Tf [(37.)] TJ ET BT 43.553 728.667 Td /F1 9.8 Tf [(Cepeda C, Colwell CS, Itri JN, Chandler SH, Levine MS \(1998\) Dopaminergic modulation of NMDA-induced whole cell )] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(currents in neostriatal neurons in slices: contribution of calcium conductances. J Neurophysiol 79:82-94.)] TJ ET BT 26.250 697.357 Td /F1 9.8 Tf [(38.)] TJ ET BT 43.553 697.357 Td /F1 9.8 Tf [(Cepeda C, Andre VM, Yamazaki I, Wu N, Kleiman-Weiner M, Levine MS \(2008\) Differential electrophysiological properties )] TJ ET BT 26.250 685.452 Td /F1 9.8 Tf [(of dopamine D1 and D2 receptor-containing striatal medium-sized spiny neurons. Eur J Neurosci 27:671-682.)] TJ ET BT 26.250 666.048 Td /F1 9.8 Tf [(39.)] TJ ET BT 43.553 666.048 Td /F1 9.8 Tf [(Ariano MA, Cepeda C, Calvert CR, Flores-Hernandez J, Hernandez-Echeagaray E, Klapstein GJ, Chandler SH, Aronin N, )] TJ ET BT 26.250 654.143 Td /F1 9.8 Tf [(DiFiglia M, Levine MS \(2005\) Striatal potassium channel dysfunction in Huntington's disease transgenic mice. J Neurophysiol )] TJ ET BT 26.250 642.238 Td /F1 9.8 Tf [(93:2565-2574.)] TJ ET BT 26.250 622.833 Td /F1 9.8 Tf [(40.)] TJ ET BT 43.553 622.833 Td /F1 9.8 Tf [(Canals JM, Pineda JR, Torres-Peraza JF, Bosch M, Martin-Ibanez R, Munoz MT, Mengod G, Ernfors P, Alberch J \(2004\) )] TJ ET BT 26.250 610.929 Td /F1 9.8 Tf [(Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic )] TJ ET BT 26.250 599.024 Td /F1 9.8 Tf [(neuronal degeneration in Huntington's disease. J Neurosci 24:7727-7739.)] TJ ET BT 26.250 579.619 Td /F1 9.8 Tf [(41.)] TJ ET BT 43.553 579.619 Td /F1 9.8 Tf [(Pang TY, Stam NC, Nithianantharajah J, Howard ML, Hannan AJ \(2006\) Differential effects of voluntary physical exercise )] TJ ET BT 26.250 567.714 Td /F1 9.8 Tf [(on behavioral and brain-derived neurotrophic factor expression deficits in Huntingtons disease transgenic mice. Neuroscience )] TJ ET BT 26.250 555.810 Td /F1 9.8 Tf [(141:569-584.)] TJ ET BT 26.250 536.405 Td /F1 9.8 Tf [(42.)] TJ ET BT 43.553 536.405 Td /F1 9.8 Tf [(Zuccato, C, Cattaneo E \(2007\) Role of brain-derived neurotrophic factor in Huntingtons disease. Prog Neurobiol 81:294-)] TJ ET BT 26.250 524.500 Td /F1 9.8 Tf [(330.)] TJ ET BT 26.250 505.095 Td /F1 9.8 Tf [(43.)] TJ ET BT 43.553 505.095 Td /F1 9.8 Tf [(Tozzi A, Tscherter A, Belcastro V, Tantucci M, Costa C, Picconi B, Centonze D, Calabresi P, Borsini F \(2007\) Interaction of )] TJ ET BT 26.250 493.191 Td /F1 9.8 Tf [(A2A adenosine and D2 dopamine receptors modulates corticostriatal glutamatergic transmission. Neuropharmacology 53:783-)] TJ ET BT 26.250 481.286 Td /F1 9.8 Tf [(789.)] TJ ET BT 26.250 461.881 Td /F1 9.8 Tf [(44.)] TJ ET BT 43.553 461.881 Td /F1 9.8 Tf [(Cummings DM, Yim MM, Alaghband Y, Malvar JS, Tsuruyama K, Joshi PR, Cepeda C, Levine MS \(2008\) The R6/2 )] TJ ET BT 26.250 449.976 Td /F1 9.8 Tf [(phenotype is CAG repeat length-dependent. Abstract Viewer/Itinerary Planner Washington, DC: Society for Neuroscience )] TJ ET BT 26.250 438.072 Td /F1 9.8 Tf [(Program No 443.11.)] TJ ET BT 26.250 418.667 Td /F1 9.8 Tf [(45.)] TJ ET BT 43.553 418.667 Td /F1 9.8 Tf [(Dragatsis I, Goldowitz D, Del Mar N, Deng YP, Meade CA, Liu L, Sun Z, Dietrich P, Yue J, Reiner A \(2009\) CAG repeat )] TJ ET BT 26.250 406.762 Td /F1 9.8 Tf [(lengths > or =335 attenuate the phenotype in the R6/2 Huntington's disease transgenic mouse. Neurobiol Dis 33:315-330.)] TJ ET BT 26.250 387.357 Td /F1 9.8 Tf [(46.)] TJ ET BT 43.553 387.357 Td /F1 9.8 Tf [(Morton AJ, Glynn D, Leavens W, Zheng Z, Faull RL, Skepper JN, Wight JM \(2009\) Paradoxical delay in the onset of )] TJ ET BT 26.250 375.453 Td /F1 9.8 Tf [(disease caused by super-long CAG repeat expansions in R6/2 mice. Neurobiol Dis 33:331-341.)] TJ ET Q q 15.000 358.072 577.500 418.928 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(36.)] TJ ET BT 43.553 759.976 Td /F1 9.8 Tf [(Watson JB, Hatami A, David H, Masliah E, Roberts K, Evans CE, Levine MS \(2009\) Alterations in corticostriatal synaptic )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(plasticity in mice overexpressing human alpha-synuclein. Neuroscience 159:501-513.)] TJ ET BT 26.250 728.667 Td /F1 9.8 Tf [(37.)] TJ ET BT 43.553 728.667 Td /F1 9.8 Tf [(Cepeda C, Colwell CS, Itri JN, Chandler SH, Levine MS \(1998\) Dopaminergic modulation of NMDA-induced whole cell )] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(currents in neostriatal neurons in slices: contribution of calcium conductances. J Neurophysiol 79:82-94.)] TJ ET BT 26.250 697.357 Td /F1 9.8 Tf [(38.)] TJ ET BT 43.553 697.357 Td /F1 9.8 Tf [(Cepeda C, Andre VM, Yamazaki I, Wu N, Kleiman-Weiner M, Levine MS \(2008\) Differential electrophysiological properties )] TJ ET BT 26.250 685.452 Td /F1 9.8 Tf [(of dopamine D1 and D2 receptor-containing striatal medium-sized spiny neurons. Eur J Neurosci 27:671-682.)] TJ ET BT 26.250 666.048 Td /F1 9.8 Tf [(39.)] TJ ET BT 43.553 666.048 Td /F1 9.8 Tf [(Ariano MA, Cepeda C, Calvert CR, Flores-Hernandez J, Hernandez-Echeagaray E, Klapstein GJ, Chandler SH, Aronin N, )] TJ ET BT 26.250 654.143 Td /F1 9.8 Tf [(DiFiglia M, Levine MS \(2005\) Striatal potassium channel dysfunction in Huntington's disease transgenic mice. J Neurophysiol )] TJ ET BT 26.250 642.238 Td /F1 9.8 Tf [(93:2565-2574.)] TJ ET BT 26.250 622.833 Td /F1 9.8 Tf [(40.)] TJ ET BT 43.553 622.833 Td /F1 9.8 Tf [(Canals JM, Pineda JR, Torres-Peraza JF, Bosch M, Martin-Ibanez R, Munoz MT, Mengod G, Ernfors P, Alberch J \(2004\) )] TJ ET BT 26.250 610.929 Td /F1 9.8 Tf [(Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic )] TJ ET BT 26.250 599.024 Td /F1 9.8 Tf [(neuronal degeneration in Huntington's disease. J Neurosci 24:7727-7739.)] TJ ET BT 26.250 579.619 Td /F1 9.8 Tf [(41.)] TJ ET BT 43.553 579.619 Td /F1 9.8 Tf [(Pang TY, Stam NC, Nithianantharajah J, Howard ML, Hannan AJ \(2006\) Differential effects of voluntary physical exercise )] TJ ET BT 26.250 567.714 Td /F1 9.8 Tf [(on behavioral and brain-derived neurotrophic factor expression deficits in Huntingtons disease transgenic mice. Neuroscience )] TJ ET BT 26.250 555.810 Td /F1 9.8 Tf [(141:569-584.)] TJ ET BT 26.250 536.405 Td /F1 9.8 Tf [(42.)] TJ ET BT 43.553 536.405 Td /F1 9.8 Tf [(Zuccato, C, Cattaneo E \(2007\) Role of brain-derived neurotrophic factor in Huntingtons disease. Prog Neurobiol 81:294-)] TJ ET BT 26.250 524.500 Td /F1 9.8 Tf [(330.)] TJ ET BT 26.250 505.095 Td /F1 9.8 Tf [(43.)] TJ ET BT 43.553 505.095 Td /F1 9.8 Tf [(Tozzi A, Tscherter A, Belcastro V, Tantucci M, Costa C, Picconi B, Centonze D, Calabresi P, Borsini F \(2007\) Interaction of )] TJ ET BT 26.250 493.191 Td /F1 9.8 Tf [(A2A adenosine and D2 dopamine receptors modulates corticostriatal glutamatergic transmission. Neuropharmacology 53:783-)] TJ ET BT 26.250 481.286 Td /F1 9.8 Tf [(789.)] TJ ET BT 26.250 461.881 Td /F1 9.8 Tf [(44.)] TJ ET BT 43.553 461.881 Td /F1 9.8 Tf [(Cummings DM, Yim MM, Alaghband Y, Malvar JS, Tsuruyama K, Joshi PR, Cepeda C, Levine MS \(2008\) The R6/2 )] TJ ET BT 26.250 449.976 Td /F1 9.8 Tf [(phenotype is CAG repeat length-dependent. Abstract Viewer/Itinerary Planner Washington, DC: Society for Neuroscience )] TJ ET BT 26.250 438.072 Td /F1 9.8 Tf [(Program No 443.11.)] TJ ET BT 26.250 418.667 Td /F1 9.8 Tf [(45.)] TJ ET BT 43.553 418.667 Td /F1 9.8 Tf [(Dragatsis I, Goldowitz D, Del Mar N, Deng YP, Meade CA, Liu L, Sun Z, Dietrich P, Yue J, Reiner A \(2009\) CAG repeat )] TJ ET BT 26.250 406.762 Td /F1 9.8 Tf [(lengths > or =335 attenuate the phenotype in the R6/2 Huntington's disease transgenic mouse. Neurobiol Dis 33:315-330.)] TJ ET BT 26.250 387.357 Td /F1 9.8 Tf [(46.)] TJ ET BT 43.553 387.357 Td /F1 9.8 Tf [(Morton AJ, Glynn D, Leavens W, Zheng Z, Faull RL, Skepper JN, Wight JM \(2009\) Paradoxical delay in the onset of )] TJ ET BT 26.250 375.453 Td /F1 9.8 Tf [(disease caused by super-long CAG repeat expansions in R6/2 mice. Neurobiol Dis 33:331-341.)] TJ ET Q q 15.000 358.072 577.500 418.928 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(36.)] TJ ET BT 43.553 759.976 Td /F1 9.8 Tf [(Watson JB, Hatami A, David H, Masliah E, Roberts K, Evans CE, Levine MS \(2009\) Alterations in corticostriatal synaptic )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(plasticity in mice overexpressing human alpha-synuclein. Neuroscience 159:501-513.)] TJ ET BT 26.250 728.667 Td /F1 9.8 Tf [(37.)] TJ ET BT 43.553 728.667 Td /F1 9.8 Tf [(Cepeda C, Colwell CS, Itri JN, Chandler SH, Levine MS \(1998\) Dopaminergic modulation of NMDA-induced whole cell )] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(currents in neostriatal neurons in slices: contribution of calcium conductances. J Neurophysiol 79:82-94.)] TJ ET BT 26.250 697.357 Td /F1 9.8 Tf [(38.)] TJ ET BT 43.553 697.357 Td /F1 9.8 Tf [(Cepeda C, Andre VM, Yamazaki I, Wu N, Kleiman-Weiner M, Levine MS \(2008\) Differential electrophysiological properties )] TJ ET BT 26.250 685.452 Td /F1 9.8 Tf [(of dopamine D1 and D2 receptor-containing striatal medium-sized spiny neurons. Eur J Neurosci 27:671-682.)] TJ ET BT 26.250 666.048 Td /F1 9.8 Tf [(39.)] TJ ET BT 43.553 666.048 Td /F1 9.8 Tf [(Ariano MA, Cepeda C, Calvert CR, Flores-Hernandez J, Hernandez-Echeagaray E, Klapstein GJ, Chandler SH, Aronin N, )] TJ ET BT 26.250 654.143 Td /F1 9.8 Tf [(DiFiglia M, Levine MS \(2005\) Striatal potassium channel dysfunction in Huntington's disease transgenic mice. J Neurophysiol )] TJ ET BT 26.250 642.238 Td /F1 9.8 Tf [(93:2565-2574.)] TJ ET BT 26.250 622.833 Td /F1 9.8 Tf [(40.)] TJ ET BT 43.553 622.833 Td /F1 9.8 Tf [(Canals JM, Pineda JR, Torres-Peraza JF, Bosch M, Martin-Ibanez R, Munoz MT, Mengod G, Ernfors P, Alberch J \(2004\) )] TJ ET BT 26.250 610.929 Td /F1 9.8 Tf [(Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic )] TJ ET BT 26.250 599.024 Td /F1 9.8 Tf [(neuronal degeneration in Huntington's disease. J Neurosci 24:7727-7739.)] TJ ET BT 26.250 579.619 Td /F1 9.8 Tf [(41.)] TJ ET BT 43.553 579.619 Td /F1 9.8 Tf [(Pang TY, Stam NC, Nithianantharajah J, Howard ML, Hannan AJ \(2006\) Differential effects of voluntary physical exercise )] TJ ET BT 26.250 567.714 Td /F1 9.8 Tf [(on behavioral and brain-derived neurotrophic factor expression deficits in Huntingtons disease transgenic mice. Neuroscience )] TJ ET BT 26.250 555.810 Td /F1 9.8 Tf [(141:569-584.)] TJ ET BT 26.250 536.405 Td /F1 9.8 Tf [(42.)] TJ ET BT 43.553 536.405 Td /F1 9.8 Tf [(Zuccato, C, Cattaneo E \(2007\) Role of brain-derived neurotrophic factor in Huntingtons disease. Prog Neurobiol 81:294-)] TJ ET BT 26.250 524.500 Td /F1 9.8 Tf [(330.)] TJ ET BT 26.250 505.095 Td /F1 9.8 Tf [(43.)] TJ ET BT 43.553 505.095 Td /F1 9.8 Tf [(Tozzi A, Tscherter A, Belcastro V, Tantucci M, Costa C, Picconi B, Centonze D, Calabresi P, Borsini F \(2007\) Interaction of )] TJ ET BT 26.250 493.191 Td /F1 9.8 Tf [(A2A adenosine and D2 dopamine receptors modulates corticostriatal glutamatergic transmission. Neuropharmacology 53:783-)] TJ ET BT 26.250 481.286 Td /F1 9.8 Tf [(789.)] TJ ET BT 26.250 461.881 Td /F1 9.8 Tf [(44.)] TJ ET BT 43.553 461.881 Td /F1 9.8 Tf [(Cummings DM, Yim MM, Alaghband Y, Malvar JS, Tsuruyama K, Joshi PR, Cepeda C, Levine MS \(2008\) The R6/2 )] TJ ET BT 26.250 449.976 Td /F1 9.8 Tf [(phenotype is CAG repeat length-dependent. 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