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In addition, they cause a severe form of migraine with aura, familial hemiplegic migraine. Moreover, <jats:italic><jats:styled-content style=\"fixed-case\">SCN<\/jats:styled-content>1A<\/jats:italic>\/Na<jats:sub>V<\/jats:sub>1.1 variants have been inferred as risk factors in other types of epilepsy. We review here the advancements obtained studying pathologic mechanisms of <jats:italic><jats:styled-content style=\"fixed-case\">SCN<\/jats:styled-content>1A<\/jats:italic>\/Na<jats:sub>V<\/jats:sub>1.1 mutations with experimental systems. We present results gained with in vitro expression systems, gene\u2010targeted animal models, and the induced pluripotent stem cell (<jats:styled-content style=\"fixed-case\">iPSC)<\/jats:styled-content> technology, highlighting advantages, limits, and pitfalls for each of these systems. Overall, the results obtained in the last two decades confirm that the initial pathologic mechanism of epileptogenic <jats:italic><jats:styled-content style=\"fixed-case\">SCN<\/jats:styled-content>1A<\/jats:italic>\/Na<jats:sub>V<\/jats:sub>1.1 mutations is loss\u2010of\u2010function of Na<jats:sub>V<\/jats:sub>1.1 leading to hypoexcitability of at least some types of \u03b3\u2010aminobutyric acid (<jats:styled-content style=\"fixed-case\">GABA)<\/jats:styled-content>ergic neurons (including cortical and hippocampal parvalbumin\u2010positive and somatostatin\u2010positive ones). Conversely, more limited results point to Na<jats:sub>V<\/jats:sub>1.1 gain\u2010of\u2010function for familial hemiplegic migraine (<jats:styled-content style=\"fixed-case\">FHM)<\/jats:styled-content> mutations. Behind these relatively simple pathologic mechanisms, an unexpected complexity has been observed, in part generated by technical issues in experimental studies and in part related to intrinsically complex pathophysiologic responses and remodeling, which yet remain to be fully disentangled.<\/jats:p>","DOI":"10.1111\/epi.14700","type":"journal-article","created":{"date-parts":[[2020,1,6]],"date-time":"2020-01-06T12:23:36Z","timestamp":1578313416000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["<i><scp>SCN<\/scp>1A<\/i>\/Na<sub>V<\/sub>1.1 channelopathies: Mechanisms in expression systems, animal models, and human <scp>iPSC<\/scp> models"],"prefix":"10.1111","volume":"60","author":[{"given":"Massimo","family":"Mantegazza","sequence":"first","affiliation":[{"name":"University Cote d'Azur (UCA) CNRS UMR7275 INSERM Institute of Molecular and Cellular Pharmacology (IPMC)  Valbonne\u2010Sophia Antipolis 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