{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T23:12:29Z","timestamp":1781305949703,"version":"3.54.1"},"reference-count":71,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T00:00:00Z","timestamp":1757548800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T00:00:00Z","timestamp":1757548800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["864243"],"award-info":[{"award-number":["864243"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["DFG DE 419\/9\u20101 | STR 865\/5\u20101"],"award-info":[{"award-number":["DFG DE 419\/9\u20101 | STR 865\/5\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006188","name":"Einstein Stiftung Berlin","doi-asserted-by":"publisher","award":["EP\u20102021\u2010621"],"award-info":[{"award-number":["EP\u20102021\u2010621"]}],"id":[{"id":"10.13039\/501100006188","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2026,1]]},"abstract":"Abstract<\/jats:title>\n \n Objective<\/jats:title>\n \n The K\n +<\/jats:sup>\n \/Cl\n \u2212<\/jats:sup>\n cotransporter (KCC2), which acts as the main Cl\n \u2212<\/jats:sup>\n extruder in the adult brain, coregulates the driving force and therewith indirectly the amount and polarity of \u03b3\u2010aminobutyric acidergic (GABAergic) currents. Whether the net effect of active KCC2 is inhibitory via such Cl\n \u2212<\/jats:sup>\n extrusion or excitatory due to the concomitant increase of K\n +<\/jats:sup>\n in the extracellular space is context\u2010dependent and difficult to predict. Consecutively, in rodent models, antiseizure\u2010 as well as seizure\u2010facilitating effects of KCC2 block have been reported. Here, we attempted to gain more insight into KCC2's role in the seizure propagation zone in human temporal neocortex.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We induced network activity in postoperative acute neocortical brain slices from humans with temporal lobe epilepsy under low Mg\n 2+<\/jats:sup>\n conditions, with and without elevated K\n +<\/jats:sup>\n , and recorded it using microelectrode arrays. We analyzed ictal\u2010like events and interictal\u2010like discharges with a developed source\u2010separating approach. Finally, we complemented these network\u2010related studies by patch\u2010clamp recordings of individual pyramidal neurons under regular ionic conditions to assess the inherent functionality of KCC2 and alternative transmembrane Cl\n \u2212<\/jats:sup>\n routes.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Modulation of KCC2 activity altered the induced network activity; KCC2 block reversibly led to substantially increased activity, preferentially in and propagating through supragranular layers. Correspondingly, enhancing KCC2 activity reduced network activity there. Almost all individual supragranular pyramidal neurons tested had functional KCC2, that is, certain Cl\n \u2212<\/jats:sup>\n extrusion capacity that was limited when loaded with higher Cl\n \u2212<\/jats:sup>\n and presented variable predominantly positive values of GABA\n A<\/jats:sub>\n receptor driving force. In addition, we found tonic inhibition that increases after prolonged KCC2 block and may either contribute to Cl\n \u2212<\/jats:sup>\n load or support Cl\n \u2212<\/jats:sup>\n extrusion in supragranular pyramidal neurons, depending on their intracellular Cl\n \u2212<\/jats:sup>\n concentration.\n <\/jats:p>\n <\/jats:sec>\n \n Significance<\/jats:title>\n Our data show that KCC2 mitigates ictal\u2010like activity in the seizure propagation zone of human neocortex, thereby further promoting KCC2 as a therapeutic target.<\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/epi.18630","type":"journal-article","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T15:02:43Z","timestamp":1757602963000},"page":"499-516","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Potassium\u2013chloride cotransporter 2 activity dampens induced ictal\u2010like activity in neocortical slices containing the seizure propagation zone of temporal lobe epilepsy patients"],"prefix":"10.1111","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-5430-8953","authenticated-orcid":false,"given":"Alice","family":"Falck","sequence":"first","affiliation":[{"name":"Center for Anatomy Institute for Cell Biology and Neurobiology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin and Humboldt\u2010Universit\u00e4t zu Berlin Berlin Germany"},{"name":"Department of Neurology With Experimental Neurology Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin and Humboldt\u2010Universit\u00e4t zu Berlin Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janna","family":"Lehnhoff","sequence":"additional","affiliation":[{"name":"Center for Anatomy Institute for Cell Biology and Neurobiology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin and 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Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4891-8921","authenticated-orcid":false,"given":"Annette","family":"Aigner","sequence":"additional","affiliation":[{"name":"Institute of Biometry and Clinical Epidemiology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin and Humboldt\u2010Universit\u00e4t zu Berlin Berlin Germany"},{"name":"Center for Stroke Research Berlin, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin and Humboldt\u2010Universit\u00e4t zu Berlin Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6941-3397","authenticated-orcid":false,"given":"Helena","family":"Radbruch","sequence":"additional","affiliation":[{"name":"Department of Neuropathology Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin and 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Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin and Humboldt\u2010Universit\u00e4t zu Berlin Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6249-629X","authenticated-orcid":false,"given":"Thilo","family":"Kalbhenn","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Evangelisches Klinikum Bethel, Universit\u00e4tsklinikum OWL der Universit\u00e4t Bielefeld Bielefeld Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8363-9576","authenticated-orcid":false,"given":"Thomas","family":"Sauvigny","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Klinik und Poliklinik f\u00fcr Neurochirurgie, Universit\u00e4tsklinikum Hamburg Eppendorf Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolf 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