{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:45:33Z","timestamp":1790646333828,"version":"4.1.0"},"reference-count":151,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2020,11,30]],"date-time":"2020-11-30T00:00:00Z","timestamp":1606694400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Intracellular chloride levels in the brain are regulated primarily through the opposing effects of two cation-chloride co-transporters (CCCs), namely K+-Cl\u2212 co-transporter-2 (KCC2) and Na+-K+-Cl\u2212 co-transporter-1 (NKCC1). These CCCs are differentially expressed throughout the course of development, thereby determining the excitatory-to-inhibitory \u03b3-aminobutyric acid (GABA) switch. GABAergic excitation (depolarisation) is important in controlling the healthy development of the nervous system; as the brain matures, GABAergic inhibition (hyperpolarisation) prevails. This developmental switch in excitability is important, as uncontrolled regulation of neuronal excitability can have implications for health. Huntington\u2019s disease (HD) is an example of a genetic disorder whereby the expression levels of KCC2 are abnormal due to mutant protein interactions. Although HD is primarily considered a motor disease, many other clinical manifestations exist; these often present in advance of any movement abnormalities. Cognitive change, in addition to sleep disorders, is prevalent in the HD population; the effect of uncontrolled KCC2 function on cognition and sleep has also been explored. Several mechanisms by which KCC2 expression is reduced have been proposed recently, thereby suggesting extensive investigation of KCC2 as a possible therapeutic target for the development of pharmacological compounds that can effectively treat HD co-morbidities. Hence, this review summarizes the role of KCC2 in the healthy and HD brain, and highlights recent advances that attest to KCC2 as a strong research and therapeutic target candidate.<\/jats:p>","DOI":"10.3390\/ijms21239142","type":"journal-article","created":{"date-parts":[[2020,11,30]],"date-time":"2020-11-30T20:10:22Z","timestamp":1606767022000},"page":"9142","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["The Therapeutic Potential of Neuronal K-Cl Co-Transporter KCC2 in Huntington\u2019s Disease and Its Comorbidities"],"prefix":"10.3390","volume":"21","author":[{"given":"Katie","family":"Andrews","sequence":"first","affiliation":[{"name":"Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Hatherly Laboratories, Exeter EX4 4PS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8126-358X","authenticated-orcid":false,"given":"Sunday Solomon","family":"Josiah","sequence":"additional","affiliation":[{"name":"Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Hatherly Laboratories, Exeter EX4 4PS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8683-509X","authenticated-orcid":false,"given":"Jinwei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Hatherly Laboratories, Exeter EX4 4PS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"C1516","DOI":"10.1152\/ajpcell.1997.273.5.C1516","article-title":"Functional characterization of the neuronal-specific K-Cl cotransporter: Implications for [K+] oregulation","volume":"273","author":"Payne","year":"1997","journal-title":"Am. 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