{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T01:10:50Z","timestamp":1793149850013,"version":"4.5.0"},"reference-count":213,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,14]],"date-time":"2022-01-14T00:00:00Z","timestamp":1642118400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:p>Intracellular chloride (Cl<jats:sup>\u2013<\/jats:sup>) levels in mature neurons must be tightly regulated for the maintenance of fast synaptic inhibition. In the mature central nervous system (CNS), synaptic inhibition is primarily mediated by gamma-amino butyric acid (GABA), which binds to Cl<jats:sup>\u2013<\/jats:sup> permeable GABA<jats:sub>A<\/jats:sub> receptors (GABA<jats:sub>A<\/jats:sub>Rs). The intracellular Cl<jats:sup>\u2013<\/jats:sup> concentration is primarily maintained by the antagonistic actions of two cation-chloride cotransporters (CCCs): Cl<jats:sup>\u2013<\/jats:sup>-importing Na<jats:sup>+<\/jats:sup>-K<jats:sup>+<\/jats:sup>-Cl<jats:sup>\u2013<\/jats:sup> co-transporter-1 (NKCC1) and Cl<jats:sup>\u2013<\/jats:sup> -exporting K<jats:sup>+<\/jats:sup>-Cl<jats:sup>\u2013<\/jats:sup> co-transporter-2 (KCC2). In mature neurons in the healthy brain, KCC2 expression is higher than NKCC1, leading to lower levels of intracellular Cl<jats:sup>\u2013<\/jats:sup>, and Cl<jats:sup>\u2013<\/jats:sup> influx upon GABA<jats:sub>A<\/jats:sub>R activation. However, in neurons of the immature brain or in neurological disorders such as epilepsy and traumatic brain injury, impaired KCC2 function and\/or enhanced NKCC1 expression lead to intracellular Cl<jats:sup>\u2013<\/jats:sup> accumulation and GABA-mediated excitation. In Huntington\u2019s disease (HD), KCC2- and NKCC1-mediated Cl<jats:sup>\u2013<\/jats:sup>-regulation are also altered, which leads to GABA-mediated excitation and contributes to the development of cognitive and motor impairments. This review summarizes the role of Cl<jats:sup>\u2013<\/jats:sup> (dys)regulation in the healthy and HD brain, with a focus on the basal ganglia (BG) circuitry and CCCs as potential therapeutic targets in the treatment of HD.<\/jats:p>","DOI":"10.3389\/fncel.2021.817013","type":"journal-article","created":{"date-parts":[[2022,1,14]],"date-time":"2022-01-14T04:34:52Z","timestamp":1642134892000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Striatal Chloride Dysregulation and Impaired GABAergic Signaling Due to Cation-Chloride Cotransporter Dysfunction in Huntington\u2019s Disease"],"prefix":"10.3389","volume":"15","author":[{"given":"Melissa","family":"Serranilla","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie A.","family":"Woodin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"6667","DOI":"10.1523\/jneurosci.4662-14.2015","article-title":"Prototypic and Arkypallidal Neurons in the Dopamine-Intact External Globus Pallidus.","volume":"35","author":"Abdi","year":"2015","journal-title":"J. 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