{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T01:35:49Z","timestamp":1793151349648,"version":"4.5.0"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,24]],"date-time":"2022-06-24T00:00:00Z","timestamp":1656028800000},"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. Cell Dev. Biol."],"abstract":"<jats:p>KCC2 is a K<jats:sup>+<\/jats:sup>-Cl<jats:sup>\u2212<\/jats:sup> cotransporter that is expressed in neurons throughout the central nervous system. Deficits in KCC2 activity have been implicated in a variety of neurological disorders, including epilepsy, chronic pain, autism spectrum disorders, and Rett syndrome. Therefore, it has been hypothesized that pharmacological potentiation of KCC2 activity could provide a treatment for these disorders. To evaluate the therapeutic potential of pharmacological KCC2 potentiation, drug-like, selective KCC2 potentiators are required. Unfortunately, the lack of such tools has greatly hampered the investigation of the KCC2 potentiation hypothesis. Herein, we describe the discovery and characterization of a new class of small-molecule KCC2 potentiator. This newly discovered class exhibits KCC2-dependent activity and a unique mechanistic profile relative to previously reported small molecules. Furthermore, we demonstrate that KCC2 potentiation by this new class of KCC2 potentiator attenuates seizure-like activity in neuronal-glial co-cultures. Together, our results provide evidence that pharmacological KCC2 potentiation, by itself, is sufficient to attenuate neuronal excitability in an <jats:italic>in vitro<\/jats:italic> model that is sensitive to anti-epileptic drugs. Our findings and chemical tools are important for evaluating the promise of KCC2 as a therapeutic target and could lay a foundation for the development of KCC2-directed therapeutics for multiple neurological disorders.<\/jats:p>","DOI":"10.3389\/fcell.2022.912812","type":"journal-article","created":{"date-parts":[[2022,6,24]],"date-time":"2022-06-24T06:33:45Z","timestamp":1656052425000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Discovery of Small Molecule KCC2 Potentiators Which Attenuate In Vitro Seizure-Like Activity in Cultured Neurons"],"prefix":"10.3389","volume":"10","author":[{"given":"Francis J.","family":"Prael III","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwangho","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brittany D.","family":"Spitznagel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary A.","family":"Sulikowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Delpire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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