{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T06:08:56Z","timestamp":1763705336839,"version":"build-2065373602"},"reference-count":66,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2017,8,7]],"date-time":"2017-08-07T00:00:00Z","timestamp":1502064000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003711","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","award":["NSC101\u20102321\u2010B\u2010001\u2010047","MOST 104\u20102811\u2010B\u2010001\u2010123","MOST 104\u20102314\u2010B\u2010039\u2010031\u2010MY2"],"award-info":[{"award-number":["NSC101\u20102321\u2010B\u2010001\u2010047","MOST 104\u20102811\u2010B\u2010001\u2010123","MOST 104\u20102314\u2010B\u2010039\u2010031\u2010MY2"]}],"id":[{"id":"10.13039\/501100003711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007300","name":"China Medical University","doi-asserted-by":"publisher","award":["CMU 104\u2010N12"],"award-info":[{"award-number":["CMU 104\u2010N12"]}],"id":[{"id":"10.13039\/501100007300","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001869","name":"Academia Sinica","doi-asserted-by":"publisher","award":["AS\u2010100\u2010TP2\u2010B02"],"award-info":[{"award-number":["AS\u2010100\u2010TP2\u2010B02"]}],"id":[{"id":"10.13039\/501100001869","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Movement Disorders"],"published-print":{"date-parts":[[2017,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p><jats:bold>Background<\/jats:bold>: Disruptions in gamma\u2010aminobutyric (GABA) acid signaling are believed to be involved in Huntington's disease pathogenesis, but the regulation of GABAergic signaling remains elusive. Here we evaluated GABAergic signaling by examining the function of GABAergic drugs in Huntington's disease and the expression of GABAergic molecules using mouse models and human brain tissues from Huntington's disease.<\/jats:p><jats:p><jats:bold>Methods<\/jats:bold>: We treated wild\u2010type and R6\/2 mice (a transgenic Huntington's disease mouse model) acutely with vehicle, diazepam, or gaboxadol (drugs that selectively target synaptic or extrasynaptic GABA<jats:sub>A<\/jats:sub> receptors) and monitored their locomotor activity. The expression levels of GABA<jats:sub>A<\/jats:sub> receptors and a major neuron\u2010specific chloride extruder (potassium\u2010chloride cotransporter\u20102) were analyzed by real\u2010time quantitative polymerase chain reaction, Western blot, and immunocytochemistry.<\/jats:p><jats:p><jats:bold>Results<\/jats:bold>: The R6\/2 mice were less sensitive to the sedative effects of both drugs, suggesting reduced function of GABA<jats:sub>A<\/jats:sub> receptors. Consistently, the expression levels of \u03b11\/\u03b12 and \u03b4 subunits were lower in the cortex and striatum of R6\/2 mice. Similar results were also found in 2 other mouse models of Huntington's disease and in Huntington's disease patients. Moreover, the interaction and expression levels of potassium\u2010chloride cotransporter\u20102 and its activator (brain\u2010type creatine kinase) were decreased in Huntington's disease neurons. These findings collectively suggest impaired chloride homeostasis, which further dampens GABA<jats:sub>A<\/jats:sub> receptor\u2010mediated inhibitory signaling in Huntington's disease brains.<\/jats:p><jats:p><jats:bold>Conclusions<\/jats:bold>: The dysregulated GABAergic responses and altered expression levels of GABA<jats:sub>A<\/jats:sub> receptors and potassium\u2010chloride cotransporter\u20102 in Huntington's disease mice appear to be authentic and may contribute to the clinical manifestations of Huntington's disease patients. \u00a9 2017 International Parkinson and Movement Disorder Society<\/jats:p>","DOI":"10.1002\/mds.27107","type":"journal-article","created":{"date-parts":[[2017,8,7]],"date-time":"2017-08-07T06:18:55Z","timestamp":1502086735000},"page":"1600-1609","source":"Crossref","is-referenced-by-count":11,"title":["Altered behavioral responses to gamma\u2010aminobutyric acid pharmacological agents in a mouse model of Huntington's disease"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8552-131X","authenticated-orcid":false,"given":"Yi\u2010Ting","family":"Hsu","sequence":"first","affiliation":[{"name":"Ph.D. Program for Translational Medicine China Medical University and Academia Sinica  Taiwan"},{"name":"Department of Neurology China Medical University Hospital Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ya\u2010Gin","family":"Chang","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience National Yang\u2010Ming University Taipei Taiwan"},{"name":"Taiwan International Graduate Program in Interdisciplinary Neuroscience National Yang\u2010Ming University and Academia Sinica Taipei Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ching\u2010Pang","family":"Chang","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences Academia Sinica Taipei Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian\u2010Jing","family":"Siew","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences Academia Sinica Taipei Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui\u2010Mei","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences Academia Sinica Taipei Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chon\u2010Haw","family":"Tsai","sequence":"additional","affiliation":[{"name":"Ph.D. Program for Translational Medicine China Medical University and Academia Sinica  Taiwan"},{"name":"Department of Neurology China Medical University Hospital Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yijuang","family":"Chern","sequence":"additional","affiliation":[{"name":"Ph.D. Program for Translational Medicine China Medical University and Academia Sinica  Taiwan"},{"name":"Institute of Biomedical Sciences Academia Sinica Taipei Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,8,7]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)60111-1"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(10)70245-3"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.25237"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000198586.85250.13"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2011.06.075"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-381328-2.00014-6"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2016.05.027"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2012.02.015"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2137-12.2013"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncir.2013.00188"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-510X(80)90103-3"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/103.1.179"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchemneu.2009.02.001"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00259-016-3324-6"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2015.09.030"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2011.08.040"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.12.012"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1625"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/44579"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/75761"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2006.02.054"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0600329103"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2005.03029.x"},{"issue":"10","key":"e_1_2_8_25_1","first-page":"976","article-title":"Flumazenil: a benzodiazepine antagonist","volume":"24","author":"Karavokiros KA","year":"1990","journal-title":"Ann Pharmacother"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3340-09.2009"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.15252\/msb.20145304"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.03.003"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1301195"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2005.03560.x"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(04)00328-X"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2010.05.001"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2013.02.006"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0028-3908(02)00174-0"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.59.3.442"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02245628"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(94)90320-4"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2004.12.016"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/0091-3057(91)90233-R"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep03738"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1994.62010070.x"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0008-14.2015"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3908-07.2008"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1016190108"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.01.008"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2464"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2014.09.010"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.37.6.916"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(79)90060-X"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.34.5.702-a"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-510X(88)90215-8"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2016.01.027"},{"key":"e_1_2_8_53_1","first-page":"2179","article-title":"Transgenic animal models for study of the pathogenesis of Huntington's disease and therapy","volume":"9","author":"Chang R","year":"2015","journal-title":"Drug Des Dev Ther"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81369-0"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/8.3.397"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/10.2.137"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1744"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1072613"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1219"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-8-203"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2934-09.2009"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep26173"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2806"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.apha.2014.11.010"},{"issue":"2","key":"e_1_2_8_65_1","first-page":"111","article-title":"Type A gamma\u2010aminobutyric acid (GABAA) receptor subunits and benzodiazepine binding: significance to clinical syndromes and their treatment","volume":"58","author":"Smith TA","year":"2001","journal-title":"Br J Biomed Sci"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2014.08.003"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005072-198511000-00003"}],"container-title":["Movement Disorders"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fmds.27107","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/movementdisorders.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mds.27107","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T12:54:05Z","timestamp":1760964845000},"score":1,"resource":{"primary":{"URL":"https:\/\/movementdisorders.onlinelibrary.wiley.com\/doi\/10.1002\/mds.27107"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8,7]]},"references-count":66,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2017,11]]}},"alternative-id":["10.1002\/mds.27107"],"URL":"https:\/\/doi.org\/10.1002\/mds.27107","archive":["Portico"],"relation":{},"ISSN":["0885-3185","1531-8257"],"issn-type":[{"type":"print","value":"0885-3185"},{"type":"electronic","value":"1531-8257"}],"subject":[],"published":{"date-parts":[[2017,8,7]]}}}