{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:29:55Z","timestamp":1792798195264,"version":"4.5.0"},"reference-count":47,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2018,10,15]],"date-time":"2018-10-15T00:00:00Z","timestamp":1539561600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000095","name":"Savoy Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000095","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Fonds de Recherche Qu\u00e9bec Sant\u00e9"},{"name":"Rare Disease Model and Mechanism network"},{"name":"Dravet Canada","id":[{"id":"https:\/\/ror.org\/00hh1sw04","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Groupe de Recherche sur le Syst\u00e8me Nerveux Central"},{"name":"Qu\u00e9bec Minist\u00e8re de l\u2019\u00c9ducation, de l\u2019Enseignement Sup\u00e9rieur et de Recherche"},{"name":"Research Center of the University of Montreal Hospital Center","id":[{"id":"https:\/\/ror.org\/0161xgx34","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2018,11]]},"abstract":"<jats:title>Summary<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      In humans, mutations of the \u03b3\u2010aminobutyric acid receptor subunit 1 (\n                      <jats:italic>GABRA1<\/jats:italic>\n                      ) cause either mild or severe generalized epilepsy. Although these epilepsy\u2010causing mutations have been shown to disrupt the receptor activity in vitro, their in vivo consequences on brain development and activity are not known. Here, we aim at unraveling the epileptogenesis mechanisms of\n                      <jats:italic>GABRA1<\/jats:italic>\n                      loss of function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We generated a\n                      <jats:italic>gabra1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      zebrafish mutant line displaying highly penetrant epileptic seizures. We sought to identify the underlying molecular mechanisms through unbiased whole transcriptomic assay of\n                      <jats:italic>gabra1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      larval brains.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Interestingly, mutant fish show fully penetrant seizures at juvenile stages that accurately mimic tonic\u2013clonic generalized seizures observed in patients. Moreover, highly penetrant seizures can be induced by light stimulation, thus providing us with the first zebrafish model in which evident epileptic seizures can be induced by nonchemical agents. Our transcriptomic assay identified misregulated genes in several pathways essential for correct brain development. More specifically, we show that the early development of the brain inhibitory network is specifically affected. Although the number of GABAergic neurons is not altered, we observed a drastic reduction in the number of inhibitory synapses and a decreased complexity of the GABAergic network. This is consistent with the disruption in expression of many genes involved in axon guidance and synapse formation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>Together with the role of GABA in neurodevelopment, our data identify a novel aspect of epileptogenesis, suggesting that the substratum of GABRA1\u2010deficiency epilepsy is a consequence of early brain neurodevelopmental defects, in particular at the level of inhibitory network wiring.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/epi.14576","type":"journal-article","created":{"date-parts":[[2018,10,16]],"date-time":"2018-10-16T01:42:38Z","timestamp":1539654158000},"page":"2061-2074","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":89,"title":["\u03b3\u2010Aminobutyric acid receptor alpha 1 subunit loss of function causes genetic generalized epilepsy by impairing inhibitory network neurodevelopment"],"prefix":"10.1111","volume":"59","author":[{"given":"\u00c9ric","family":"Samarut","sequence":"first","affiliation":[{"name":"Department of Neurosciences Research Center of the University of Montreal Hospital Center University of Montreal Montreal Quebec Canada"},{"name":"DanioDesign Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amrutha","family":"Swaminathan","sequence":"additional","affiliation":[{"name":"Department of Neurosciences Research Center of the University of Montreal Hospital Center University of Montreal Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rapha\u00eblle","family":"Rich\u00e9","sequence":"additional","affiliation":[{"name":"Department of Neurosciences Research Center of the University of Montreal Hospital Center University of Montreal Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meijiang","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Neurosciences Research Center of the University of Montreal Hospital Center University of Montreal Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahma","family":"Hassan\u2010Abdi","sequence":"additional","affiliation":[{"name":"National Institute of Health and Medical Research U1141 Paris France"},{"name":"Paris Diderot University Sorbonne Paris Cit\u00e9 Mixed Research Unit of Sciences (UMRS) 1141 Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sol\u00e8ne","family":"Renault","sequence":"additional","affiliation":[{"name":"National Institute of Health and Medical Research U1141 Paris France"},{"name":"Paris Diderot University Sorbonne Paris Cit\u00e9 Mixed Research Unit of Sciences (UMRS) 1141 Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Allard","sequence":"additional","affiliation":[{"name":"Department of Neurosciences Research Center of the University of Montreal Hospital Center University of Montreal Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liselotte","family":"Dufour","sequence":"additional","affiliation":[{"name":"Familiprix Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Cossette","sequence":"additional","affiliation":[{"name":"Department of Neurosciences Research Center of the University of Montreal Hospital Center University of Montreal Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Soussi\u2010Yanicostas","sequence":"additional","affiliation":[{"name":"National Institute of Health and Medical Research U1141 Paris France"},{"name":"Paris Diderot University Sorbonne Paris Cit\u00e9 Mixed Research Unit of Sciences (UMRS) 1141 Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Drapeau","sequence":"additional","affiliation":[{"name":"Department of Neurosciences Research Center of the University of Montreal Hospital Center University of Montreal Montreal Quebec Canada"},{"name":"DanioDesign Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,10,15]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2005.00309.x"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4757-6376-8_7"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-444-63326-2.00003-X"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng885"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/med\/9780199746545.003.0055"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000000291"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1440-1681.1999.03151.x"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3947"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn920"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-014-9560-1"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2017.10.022"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.102.036665"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200523625"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/aja.1002030302"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1364\/BOE.7.001656"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-016-2881-1"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2018.04.061"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.21888"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2004.11.031"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12354"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3410"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.211"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2007.01.011"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M703957200"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.656173"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.12.007"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-02-00709.2000"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1042\/bst0310889"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0989-13.2013"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2014.02.005"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3003"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2012.03.004"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-4886(03)00035-9"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0802390105"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.12331"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf5206"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2014.08.013"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awt068"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02740750"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1097\/FPC.0000000000000000"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-00196-7"},{"key":"e_1_2_8_43_1","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1212\/WNL.86.16_supplement.P5.146","article-title":"Exome sequencing identifies dual mutations in calcium signaling genes GNAO1 and ATP2B3 in a patient with early infantile epileptic encephalopathy (EIEE)","volume":"86","author":"Ueda K","year":"2016","journal-title":"Neurology"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3144"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1003072107"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36761"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.10.012"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M308778200"}],"container-title":["Epilepsia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fepi.14576","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/epi.14576","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/epi.14576","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/epi.14576","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T07:20:54Z","timestamp":1720682454000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/epi.14576"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10,15]]},"references-count":47,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2018,11]]}},"alternative-id":["10.1111\/epi.14576"],"URL":"https:\/\/doi.org\/10.1111\/epi.14576","archive":["Portico"],"relation":{},"ISSN":["0013-9580","1528-1167"],"issn-type":[{"value":"0013-9580","type":"print"},{"value":"1528-1167","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,10,15]]},"assertion":[{"value":"2018-06-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-09-14","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-10-15","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}