{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T05:24:27Z","timestamp":1788326667835,"version":"build-2803163510"},"reference-count":112,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T00:00:00Z","timestamp":1733788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>KCC2 is CNS neuron-specific chloride extruder, essential for the establishment and maintenance of the transmembrane chloride gradient, thereby enabling synaptic inhibition within the CNS. Herein, we highlight KCC2 hypofunction as a fundamental and conserved pathology contributing to neuronal circuit excitation\/inhibition (E\/I) imbalances that underly epilepsies, chronic pain, neuro-developmental\/-traumatic\/-degenerative\/-psychiatric disorders. Indeed, downstream of both acquired and genetic factors, multiple pathologies (e.g., hyperexcitability and inflammation) converge to impair KCC2-dependent inhibition in CNS. When KCC2 hypofunction occurs, affected neurons are disinhibited due to impaired inhibitory responses to GABA\/glycine. This causes neuronal hyperexcitability, disinhibition within neuron circuits, and disrupted neurological functions. More recently, KCC2 was identified as a genetically-validated target for epilepsy, intellectual disability, and autism spectrum disorder, and pathogenic mutations in human SLC12A5 gene were linked to psychiatric\/mood disorders. The broad therapeutic utility of KCC2-upmodulating drugs relates to its critical role in determining inhibitory activity of GABAergic neurotransmission, a mechanism widely targeted by several drugs. However, in cases of KCC2 hypofunction GABAergic neurotransmission can be depolarizing\/excitatory, thereby impairing endogenous neuronal inhibition while also limiting the effectiveness of existing therapeutics targeting\/requiring GABAergic pathway inhibition. Several preclinical reports have shown that KCC2 upmodulating treatments rescue and increase the efficacy of anti-seizure and analgesic medications. Thus, a first-in-class KCC2-potentiating therapy would provide a novel mechanism for restoring physiological CNS inhibition and addressing drug resistance in patients with E\/I imbalance pathologies. Herein, we discuss progress toward and further work needed to develop the first-in-class KCC2 therapeutics to treat neurological disorder patients.<\/jats:p>","DOI":"10.3389\/fnmol.2024.1503070","type":"journal-article","created":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T06:35:39Z","timestamp":1733812539000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Development of KCC2 therapeutics to treat neurological disorders"],"prefix":"10.3389","volume":"17","author":[{"given":"Shilpa D.","family":"Kadam","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shane V.","family":"Hegarty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,12,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abo0689","article-title":"Switch of serotonergic descending inhibition into facilitation by a spinal chloride imbalance in neuropathic pain.","volume":"8","author":"Aby","year":"2022","journal-title":"Sci. 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