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Na\u2010K\u20102Cl cotransporter\u20101 is a key molecule that controls \u03b3<jats:italic>\u2010aminobutyric acid<\/jats:italic>\u2010ergic signaling. However, the role of Na\u2010K\u20102Cl cotransporter\u20101 and efficacy of \u03b3<jats:italic>\u2010aminobutyric acid<\/jats:italic>\u2010ergic transmission remain unknown in Huntington's disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We determined the levels of Na\u2010K\u20102Cl cotransporter\u20101 in brain tissue from Huntington's disease mice and patients by real\u2010time quantitative polymerase chain reaction, western blot, and immunocytochemistry. Gramicidin\u2010perforated patch\u2010clamp recordings were used to measure the <jats:italic>E<\/jats:italic><jats:sub>\u03b3<jats:italic>\u2010aminobutyric acid<\/jats:italic><\/jats:sub> in striatal brain slices. To inhibit Na\u2010K\u20102Cl cotransporter\u20101 activity, R6\/2 mice were treated with an intraperitoneal injection of bumetanide or adeno\u2010associated virus\u2010mediated delivery of Na\u2010K\u20102Cl cotransporter\u20101 short\u2010hairpin RNA into the striatum. Motor behavior assays were employed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Expression of Na\u2010K\u20102Cl cotransporter\u20101 was elevated in the striatum of R6\/2 and Hdh<jats:sup>150Q\/7Q<\/jats:sup> mouse models. An increase in Na\u2010K\u20102Cl cotransporter\u20101 transcripts was also found in the caudate nucleus of Huntington's disease patients. Accordingly, a depolarizing shift of <jats:italic>E<\/jats:italic><jats:sub>\u03b3<jats:italic>\u2010aminobutyric acid<\/jats:italic><\/jats:sub> was detected in the striatum of R6\/2 mice. Expression of the mutant <jats:italic>huntingtin<\/jats:italic> in astrocytes and neuroinflammation were necessary for enhanced expression of Na\u2010K\u20102Cl cotransporter\u20101 in HD mice. Notably, pharmacological or genetic inhibition of Na\u2010K\u20102Cl cotransporter\u20101 rescued the motor deficits of R6\/2 mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings demonstrate that aberrant \u03b3<jats:italic>\u2010aminobutyric acid<\/jats:italic>\u2010ergic signaling and enhanced Na\u2010K\u20102Cl cotransporter\u20101 contribute to the pathogenesis of Huntington's disease and identify a new therapeutic target for the potential rescue of motor dysfunction in patients with Huntington's disease. \u00a9 2019 International Parkinson and Movement Disorder Society<\/jats:p><\/jats:sec>","DOI":"10.1002\/mds.27651","type":"journal-article","created":{"date-parts":[[2019,3,6]],"date-time":"2019-03-06T13:44:45Z","timestamp":1551879885000},"page":"845-857","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Enhanced Na<sup>+<\/sup>\u2010K<sup>+<\/sup>\u20102Cl<sup>\u2010<\/sup> cotransporter 1 underlies motor dysfunction in huntington's disease"],"prefix":"10.1002","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8552-131X","authenticated-orcid":false,"given":"Yi\u2010Ting","family":"Hsu","sequence":"first","affiliation":[{"name":"PhD Program for Translational Medicine China Medical University and Academia Sinica  Taipei 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 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