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Here, we examined the therapeutic efficacy of <jats:styled-content style=\"fixed-case\">KCNQ<\/jats:styled-content> channel activation by retigabine in preventing seizures and neurocardiac dysfunction in 2 potassium channelopathy mouse models of epilepsy with differing severity that have been associated with increased risk of sudden unexpected death in epilepsy (<jats:styled-content style=\"fixed-case\">SUDEP<\/jats:styled-content>): the <jats:italic>Kcna1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> model of severe epilepsy and the <jats:italic>Kcnq1<\/jats:italic><jats:sup><jats:italic>A340E\/A340E<\/jats:italic><\/jats:sup> model of mild epilepsy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A combination of behavioral, seizure threshold, electrophysiologic, and gene expression analyses was used to determine the effects of <jats:styled-content style=\"fixed-case\">KCNQ<\/jats:styled-content> activation in mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Behaviorally, <jats:italic>Kcna1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice exhibited unexpected hyperexcitability instead of the expected sedative\u2010like response. In flurothyl\u2010induced seizure tests, <jats:styled-content style=\"fixed-case\">KCNQ<\/jats:styled-content> activation decreased seizure latency by \u226550% in <jats:italic>Kcnq1<\/jats:italic> strain mice but had no effect in the <jats:italic>Kcna1<\/jats:italic> strain, suggesting the influence of genetic background. However, in simultaneous electroencephalography and electrocardiography recordings, <jats:styled-content style=\"fixed-case\">KCNQ<\/jats:styled-content> activation significantly reduced spontaneous seizure frequency in <jats:italic>Kcna1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice by ~60%. In <jats:italic>Kcnq1<\/jats:italic><jats:sup><jats:italic>A340E\/A340E<\/jats:italic><\/jats:sup> mice, <jats:styled-content style=\"fixed-case\">KCNQ<\/jats:styled-content> activation produced adverse cardiac effects including profound bradycardia and abnormal increases in heart rate variability and atrioventricular conduction blocks. Analyses of <jats:italic>Kcnq2<\/jats:italic> and <jats:italic>Kcnq3 <\/jats:italic><jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content> levels revealed significantly elevated <jats:italic>Kcnq2<\/jats:italic> expression in <jats:italic>Kcna1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> brains, suggesting that drug target alterations may contribute to the altered drug responses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>This study shows that treatment strategies in channelopathy may have unexpected outcomes and that effective rebalancing of channel defects requires improved understanding of channel interactions at the circuit and tissue levels. The efficacy of <jats:styled-content style=\"fixed-case\">KCNQ<\/jats:styled-content> channel activation and manifestation of adverse effects were greatly affected by genetic background, potentially limiting <jats:styled-content style=\"fixed-case\">KCNQ<\/jats:styled-content> modulation as a way to prevent neurocardiac dysfunction in epilepsy and thereby <jats:styled-content style=\"fixed-case\">SUDEP<\/jats:styled-content> risk. Our data also uncover a potential role for <jats:styled-content style=\"fixed-case\">KCNQ<\/jats:styled-content>2\u20105 channels in autonomic control of chronotropy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.13978","type":"journal-article","created":{"date-parts":[[2017,12,19]],"date-time":"2017-12-19T06:28:36Z","timestamp":1513664916000},"page":"358-368","source":"Crossref","is-referenced-by-count":19,"title":["Pharmacogenetics of <scp>KCNQ<\/scp> channel activation in 2 potassium channelopathy mouse models of epilepsy"],"prefix":"10.1111","volume":"59","author":[{"given":"Stephanie L.","family":"Vanhoof\u2010Villalba","sequence":"first","affiliation":[{"name":"Department of Cellular Biology and Anatomy Louisiana State University Health Sciences Center Shreveport LA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole M.","family":"Gautier","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Anatomy Louisiana State University Health Sciences Center Shreveport LA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vikas","family":"Mishra","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Anatomy Louisiana State University Health Sciences Center Shreveport LA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward","family":"Glasscock","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Anatomy Louisiana State University Health Sciences Center Shreveport LA 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