{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T13:50:34Z","timestamp":1791640234306,"version":"4.3.4"},"reference-count":56,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,4,3]],"date-time":"2020-04-03T00:00:00Z","timestamp":1585872000000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["MH110448"],"award-info":[{"award-number":["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":["NS 040337"],"award-info":[{"award-number":["NS 040337"]}],"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":["NS044370"],"award-info":[{"award-number":["NS044370"]}],"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":["NS072162"],"award-info":[{"award-number":["NS072162"]}],"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":["NS110863"],"award-info":[{"award-number":["NS110863"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2020,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Neurosteroids regulate neuronal excitability by potentiating <jats:italic>\u03b3<\/jats:italic>\u2010aminobutyric acid type\u2010A receptors (GABARs). In animal models of temporal lobe epilepsy, the neurosteroid sensitivity of GABARs is diminished and GABAR subunit composition is altered. We tested whether similar changes occur in patients with epilepsy and if depolarization\u2010induced increases in neuronal activity can replicate this effect.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We determined GABAR <jats:italic>\u03b1<\/jats:italic>4 subunit expression in cortical tissue resected from pediatric epilepsy patients. Modulation of human GABARs by allopregnanolone and Ro15\u20104513 was measured in <jats:italic>Xenopus<\/jats:italic> oocytes using whole\u2010cell patch clamp. To extend the findings obtained using tissue from epilepsy patients, we evaluated GABAR expression and modulation by allopregnanolone and Ro15\u20104513 in cultured rat hippocampal neurons exposed to high extracellular potassium (HK) to increase neuronal activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Expression of \u03b14 subunits was increased in pediatric cortical epilepsy specimens encompassing multiple pathologies. The potentiation of GABA\u2010evoked currents by the neurosteroid allopregnanolone was decreased in <jats:italic>Xenopus<\/jats:italic> oocytes expressing GABARs isolated from epilepsy patients. Furthermore, receptors isolated from epilepsy but not control tissue were sensitive to potentiation by Ro15\u20104513, indicating higher expression of <jats:italic>\u03b1<\/jats:italic><jats:sub>4<\/jats:sub><jats:italic>\u03b2<\/jats:italic><jats:sub>x<\/jats:sub><jats:italic>\u03b3<\/jats:italic><jats:sub>2<\/jats:sub> subunit\u2010containing receptors. Correspondingly, increasing the activity of cultured rat hippocampal neurons reduced allopregnanolone potentiation of miniature inhibitory postsynaptic currents (mIPSCs), increased modulation of tonic GABAR current by Ro15\u20104513, upregulated the surface expression of\u00a0<jats:italic>\u03b1<\/jats:italic>4 and <jats:italic>\u03b3<\/jats:italic>2 subunits, and increased the colocalization of <jats:italic>\u03b1<\/jats:italic>4 and <jats:italic>\u03b3<\/jats:italic>2 subunit immunoreactivity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>These findings suggest that seizure activity\u2010induced upregulation of <jats:italic>\u03b1<\/jats:italic><jats:sub>4<\/jats:sub><jats:italic>\u03b2<\/jats:italic><jats:sub>x<\/jats:sub><jats:italic>\u03b3<\/jats:italic><jats:sub>2<\/jats:sub> subunit\u2010containing GABARs could affect the anticonvulsant actions of neurosteroids.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51023","type":"journal-article","created":{"date-parts":[[2020,4,3]],"date-time":"2020-04-03T15:09:54Z","timestamp":1585926594000},"page":"527-542","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Reduced neurosteroid potentiation of GABA<sub>A<\/sub> receptors in epilepsy and depolarized hippocampal neurons"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3524-2061","authenticated-orcid":false,"given":"Suchitra","family":"Joshi","sequence":"first","affiliation":[{"name":"Department of Neurology University of Virginia Charlottesville Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William H.","family":"Roden","sequence":"additional","affiliation":[{"name":"Seattle Children\u2019s Research Institute Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8608-1352","authenticated-orcid":false,"given":"Jaideep","family":"Kapur","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Virginia Charlottesville Virginia"},{"name":"Department of Neuroscience University of Virginia Charlottesville Virginia"},{"name":"UVA Brain Institute University of Virginia Charlottesville Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura A.","family":"Jansen","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Virginia Charlottesville Virginia"},{"name":"Seattle Children\u2019s Research Institute Seattle Washington"},{"name":"Department of Neurology Washington University School of Medicine St. Louis Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,4,3]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1703"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-6355-3_7"},{"key":"e_1_2_7_4_1","first-page":"1223","article-title":"Anticonvulsant activity of neurosteroids: correlation with GABA\u2010evoked chloride current potentiation","volume":"270","author":"Kokate TG","year":"1994","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10508"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1528-1157.2001.10100.x"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2017.12.009"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21989"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2010.01.009"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.13999"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2006.05012.x"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2010.07156.x"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.2001.00453.x"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2010.07.016"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4141-07.2007"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1555-07.2007"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0920-1211(98)00046-1"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.1162396"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2877-04.2004"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a005736"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.10.008"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/36103"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn1677"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4476-11.2011"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.2003.02597.x"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2003.059246"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.13660"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.12771"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.1997.77.4.1924"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.192445299"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2008.05.011"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2009.01.008"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-0270(91)90128-M"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2009.02491.x"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3426-07.2008"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0900-05.2005"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2004.09.056"},{"key":"e_1_2_7_38_1","first-page":"670","article-title":"Functional characterization of human GABAA receptors containing the 4 subunit","volume":"50","author":"Wafford KA","year":"1996","journal-title":"Mol Pharmacol"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0704459"},{"key":"e_1_2_7_40_1","first-page":"768","article-title":"Mutagenesis of the rat 1 subunit of the GABAA receptor reveals the importance of residue 101 in determining the allosteric effects of benzodiazepine site ligands","volume":"56","author":"Dunn SM","year":"1999","journal-title":"Mol Pharmacol"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-31-10013.2003"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2011.10.028"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2009.02.017"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2018.02.031"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv245"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/2661"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(97)00145-0"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2015.02.024"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.13705"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/0920-1211(93)90009-V"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.271.5247.369"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.22696"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.14574"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2016.07.014"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2005.11.002"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0704795"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2435457100"}],"container-title":["Annals of Clinical and Translational Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Facn3.51023","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.51023","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/acn3.51023","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.51023","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,7]],"date-time":"2023-09-07T09:31:25Z","timestamp":1694079085000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/acn3.51023"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4]]},"references-count":56,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2020,4]]}},"alternative-id":["10.1002\/acn3.51023"],"URL":"https:\/\/doi.org\/10.1002\/acn3.51023","archive":["Portico"],"relation":{},"ISSN":["2328-9503","2328-9503"],"issn-type":[{"value":"2328-9503","type":"print"},{"value":"2328-9503","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4]]},"assertion":[{"value":"2019-11-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-03-10","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-04-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}