{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T04:49:23Z","timestamp":1789274963089,"version":"build-2803163510"},"reference-count":25,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T00:00:00Z","timestamp":1701216000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100002736","name":"Citizens United for Research in Epilepsy","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002736","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009712","name":"Dravet Syndrome Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009712","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 082635"],"award-info":[{"award-number":["R01 082635"]}],"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 NS121718"],"award-info":[{"award-number":["R01 NS121718"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2024,1]]},"abstract":"Abstract<\/jats:title>\n \n Objective<\/jats:title>\n \n \u03b3\u2010Aminobutyric acid type A (GABA\n A<\/jats:sub>\n ) receptor subunit gene mutations are major causes of various epilepsy syndromes, including severe kinds such as Dravet syndrome. Although the GABA\n A<\/jats:sub>\n receptor is a major target for antiseizure medications, treating GABA\n A<\/jats:sub>\n receptor mutations with receptor channel modulators is ineffective. Here, we determined the effect of a novel treatment with 4\u2010phenylbutyrate (PBA) in\n Gabrg2<\/jats:italic>\n \n +\/Q390X<\/jats:italic>\n <\/jats:sup>\n knockin mice associated with Dravet syndrome.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We used biochemistry in conjunction with differential tagging of the wild\u2010type and the mutant alleles, live brain slice surface biotinylation, microsome isolation, patch\u2010clamp whole\u2010cell recordings, and video\u2010monitoring synchronized electroencephalographic (EEG) recordings in\n Gabrg2<\/jats:italic>\n \n +\/Q390X<\/jats:italic>\n <\/jats:sup>\n mice to determine the effect of PBA in\u00a0vitro with recombinant GABA\n A<\/jats:sub>\n receptors and in\u00a0vivo with knockin mice.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n We found that PBA reduced the mutant \u03b32(Q390X) subunit protein aggregates, enhanced the wild\u2010type GABA\n A<\/jats:sub>\n receptor subunits' trafficking, and increased the membrane expression of the wild\u2010type receptors. PBA increased the current amplitude of GABA\u2010evoked current in human embryonic kidney 293T cells and the neurons bearing the \u03b32(Q390X) subunit protein. PBA also proved to reduce endoplasmic reticulum (ER) stress caused by the mutant \u03b32(Q390X) subunit protein, as well as mitigating seizures and EEG abnormalities in the\n Gabrg2<\/jats:italic>\n \n +\/Q390X<\/jats:italic>\n <\/jats:sup>\n mice.\n <\/jats:p>\n <\/jats:sec>\n \n Significance<\/jats:title>\n \n This research has unveiled a promising and innovative approach for treating epilepsy linked to GABA\n A<\/jats:sub>\n receptor mutations through an unconventional antiseizure mechanism. Rather than directly modulating the affected mutant channel, PBA facilitates the folding and transportation of wild\u2010type receptor subunits to the cell membrane and synapse. Combining these findings with our previous study, which demonstrated PBA's efficacy in restoring GABA transporter 1 (encoded by\n SLC6A1<\/jats:italic>\n ) function, we propose that PBA holds significant potential for a wide range of genetic epilepsies. Its ability to target shared molecular pathways involving mutant protein ER retention and impaired protein membrane trafficking suggests broad application in treating such conditions.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/epi.17779","type":"journal-article","created":{"date-parts":[[2023,9,25]],"date-time":"2023-09-25T05:00:03Z","timestamp":1695618003000},"page":"204-217","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["4\u2010Phenylbutyrate promoted wild\u2010type \u03b3\u2010aminobutyric acid type A receptor trafficking, reduced endoplasmic reticulum stress, and mitigated seizures in\n \n Gabrg2\n +\/Q390X<\/sup>\n <\/i>\n mice associated with Dravet syndrome"],"prefix":"10.1111","volume":"65","author":[{"given":"Wangzhen","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Neurology Vanderbilt University Medical Center Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carson","family":"Flamm","sequence":"additional","affiliation":[{"name":"Department of Neurology Vanderbilt University Medical Center Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiden J.","family":"Delahanty","sequence":"additional","affiliation":[{"name":"Department of Neurology Vanderbilt University Medical Center Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmett","family":"Casteel","sequence":"additional","affiliation":[{"name":"Department of Neurology Vanderbilt University Medical Center Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marshall","family":"Biven","sequence":"additional","affiliation":[{"name":"Department of Neurology Vanderbilt University Medical Center Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa B.","family":"DeLeeuw","sequence":"additional","affiliation":[{"name":"Department of Neurology Vanderbilt University Medical Center Nashville Tennessee USA"},{"name":"Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology Meharry Medical College Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Poliquin","sequence":"additional","affiliation":[{"name":"Department of Neurology Vanderbilt University Medical Center Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald","family":"Nwosu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Vanderbilt University Medical Center Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karishma","family":"Randhave","sequence":"additional","affiliation":[{"name":"Department of Neurology Vanderbilt University Medical Center Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1079-5436","authenticated-orcid":false,"given":"Jing\u2010Qiong","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Neurology Vanderbilt University Medical Center Nashville Tennessee USA"},{"name":"Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology Meharry Medical College Nashville Tennessee USA"},{"name":"Department of Pharmacology Vanderbilt University Medical Center Nashville Tennessee USA"},{"name":"Vanderbilt Brain Institute Vanderbilt University Medical Center Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,11,29]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2016.0449"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0501\u201046"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1086\/338710"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1523\/jneurosci.4772\u201008.2009"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4024"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddw168"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12439"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2019.04.006"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.202200222"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcac144"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010018\u201006507\u20104"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab207"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1523\/jneurosci.2717\u201004.2004"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1523\/jneurosci.4512\u201008.2009"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2019.112973"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2022.105810"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13041\u2010020\u201000612\u20106"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb882"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1523\/jneurosci.2320\u201010.2010"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00063.2021"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.16670"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M700303\u2010MCP200"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2009.03.002"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1080\/13550280290100699"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/12207"}],"container-title":["Epilepsia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/epi.17779","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,14]],"date-time":"2024-02-14T09:29:56Z","timestamp":1707902996000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/epi.17779"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,29]]},"references-count":25,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2024,1]]}},"alternative-id":["10.1111\/epi.17779"],"URL":"https:\/\/doi.org\/10.1111\/epi.17779","archive":["Portico"],"relation":{},"ISSN":["0013-9580","1528-1167"],"issn-type":[{"value":"0013-9580","type":"print"},{"value":"1528-1167","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,29]]},"assertion":[{"value":"2023-04-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication 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