{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T15:24:53Z","timestamp":1787585093570,"version":"build-2736575974"},"reference-count":47,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2023,10,24]],"date-time":"2023-10-24T00:00:00Z","timestamp":1698105600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003837","name":"Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009666","name":"Salt Science Research Foundation","doi-asserted-by":"publisher","award":["2138"],"award-info":[{"award-number":["2138"]}],"id":[{"id":"10.13039\/100009666","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>A pathological excitatory action of the major inhibitory neurotransmitter \u03b3\u2010aminobutyric acid (GABA) has been observed in epilepsy. Blocking the Cl<jats:sup>\u2212<\/jats:sup> importer NKCC1 with bumetanide is expected to reduce the neuronal intracellular Cl<jats:sup>\u2212<\/jats:sup> concentration ([Cl<jats:sup>\u2212<\/jats:sup>]<jats:sub>i<\/jats:sub>) and thereby attenuate the excitatory GABA response. Accordingly, several clinical trials of bumetanide for epilepsy were conducted. Although NKCC1 is expressed in both neurons and glial cells, an involvement of glial NKCC1 in seizures has not yet been reported. Astrocytes maintain high [Cl<jats:sup>\u2212<\/jats:sup>]<jats:sub>i<\/jats:sub> with NKCC1, and this gradient promotes Cl<jats:sup>\u2212<\/jats:sup> efflux via the astrocytic GABA<jats:sub>A<\/jats:sub> receptor (GABA<jats:sub>A<\/jats:sub>R). This Cl<jats:sup>\u2212<\/jats:sup> efflux buffers the synaptic cleft Cl<jats:sup>\u2212<\/jats:sup> concentration to maintain the postsynaptic Cl<jats:sup>\u2212<\/jats:sup> gradient during intense firing of GABAergic neurons, thereby sustaining its inhibitory action during seizure. In this study, we investigated the function of astrocytic NKCC1 in modulating the postsynaptic action of GABA in acute seizure models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used the astrocyte\u2010specific conditional NKCC1 knockout (AstroNKCC1KO) mice. The seizurelike events (SLEs) in CA1 pyramidal neurons were triggered by tetanic stimulation of stratum radiatum in acute hippocampus slices. The SLE underlying GABA<jats:sub>A<\/jats:sub>R\u2010mediated depolarization was evaluated by applying the GABA<jats:sub>A<\/jats:sub>R antagonist bicuculline. The pilocarpine\u2010induced seizure in\u00a0vivo was monitored in adult mice by the Racine scale. The SLE duration and tetanus stimulation intensity threshold and seizure behavior in AstroNKCC1KO mice and wild\u2010type (WT) mice were compared.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The AstroNKCC1KO mice were prone to seizures with lower threshold and longer duration of SLEs and larger GABA<jats:sub>A<\/jats:sub>R\u2010mediated depolarization underlying the SLEs, accompanied by higher Racine\u2010scored seizures. Bumetanide reduced these indicators of seizure in AstroNKCC1KO mice (which still express neuronal NKCC1), but not in the WT, both in\u00a0vitro and in\u00a0vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Astrocytic NKCC1 inhibits GABA\u2010mediated excitatory action during seizures, whereas neuronal NKCC1 has the converse effect, suggesting opposing actions of bumetanide on these cells.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.17784","type":"journal-article","created":{"date-parts":[[2023,10,2]],"date-time":"2023-10-02T04:04:40Z","timestamp":1696219480000},"page":"3389-3403","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Astrocytic <scp>NKCC1<\/scp> inhibits seizures by buffering Cl<sup>\u2212<\/sup> and antagonizing neuronal <scp>NKCC1<\/scp> at GABAergic synapses"],"prefix":"10.1111","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0059-7113","authenticated-orcid":false,"given":"Trong Dao","family":"Nguyen","sequence":"first","affiliation":[{"name":"Department of Neurophysiology Hamamatsu University School of Medicine  Hamamatsu Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7413-1359","authenticated-orcid":false,"given":"Masaru","family":"Ishibashi","sequence":"additional","affiliation":[{"name":"Department of Neurophysiology Hamamatsu University School of Medicine  Hamamatsu Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7982-3525","authenticated-orcid":false,"given":"Adya Saran","family":"Sinha","sequence":"additional","affiliation":[{"name":"Department of Neurophysiology Hamamatsu University School of Medicine  Hamamatsu 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