{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T14:25:54Z","timestamp":1787149554792,"version":"build-2736575974"},"reference-count":35,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["P50 HD103525"],"award-info":[{"award-number":["P50 HD103525"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 MH110448"],"award-info":[{"award-number":["R01 MH110448"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS056872"],"award-info":[{"award-number":["R01 NS056872"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R21 NS133508"],"award-info":[{"award-number":["R21 NS133508"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Drug\u2010resistant epilepsy is a common, severe manifestation of the genetic disorder tuberous sclerosis complex (TSC). Although significant mechanistic and therapeutic advances have been made in TSC, treatments for seizures remain largely ineffective. Decreased expression of the potassium\u2013chloride cotransporter KCC2 is associated with depolarizing \u03b3\u2010aminobutyric acid (GABA) signaling and increased neuronal excitability in the immature brain and in certain pathological states. In this study, we investigated abnormalities in KCC2 expression and function in a mouse model of TSC\u2010related epilepsy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Tsc1<\/jats:italic>\n                      <jats:sup>GFAP<\/jats:sup>\n                      CKO mice were used to investigate KCC2 expression by Western blotting and immunohistochemistry. The effects of KCC2 pharmacological modulators on KCC2 expression and seizures in\n                      <jats:italic>Tsc1<\/jats:italic>\n                      <jats:sup>GFAP<\/jats:sup>\n                      CKO mice were tested by Western blotting and video\u2010electroencephalography.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      KCC2 expression was decreased in\n                      <jats:italic>Tsc1<\/jats:italic>\n                      <jats:sup>GFAP<\/jats:sup>\n                      CKO mice compared with controls, including prior to the onset of seizures. The decrease in KCC2 expression was reversed by the mTOR inhibitor rapamycin as well as select KCC2 modulators. These KCC2 modulators also decreased seizures in\n                      <jats:italic>Tsc1<\/jats:italic>\n                      <jats:sup>GFAP<\/jats:sup>\n                      CKO mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>Decreased KCC2 expression may lead to impaired GABAergic inhibition and increased neuronal excitability, contributing to epileptogenesis in TSC. Potentiation of KCC2 expression may represent a novel, effective therapeutic approach for epilepsy in TSC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/epi.70434","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T13:38:32Z","timestamp":1787146712000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Abnormal\n                    <scp>KCC2<\/scp>\n                    expression and function in a mouse model of epilepsy and tuberous sclerosis complex"],"prefix":"10.1002","author":[{"given":"Dongjun","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Neurology Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lirong","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Neurology Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas R.","family":"Rensing","sequence":"additional","affiliation":[{"name":"Department of Neurology Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura A.","family":"Jansen","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Virginia  Charlottesville Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3796-743X","authenticated-orcid":false,"given":"Michael","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Neurology Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/S0140-6736(08)61279-9","article-title":"Tuberous sclerosis","volume":"372","author":"Curatolo P","year":"2008","journal-title":"Lancet"},{"key":"e_1_2_11_3_1","doi-asserted-by":"crossref","first-page":"16035","DOI":"10.1038\/nrdp.2016.35","article-title":"Tuberous sclerosis complex","volume":"2","author":"Henske EP","year":"2016","journal-title":"Nat Rev Dis Primers"},{"key":"e_1_2_11_4_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.neuropharm.2019.107908","article-title":"Modifying genetic epilepsies\u2014results from studies on tuberous sclerosis complex","volume":"166","author":"Jozwiak 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