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A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients

Sun, Yishan and Pasca, Sergiu P. and Portmann, Thomas and Goold, Carleton and Worringer, Katie and Guan, Wendy and Chan, Karen C. and Gai, Hui and Vogt, Daniel and Chen, Ying-Jiun J. and Mao, Rong and Chan, Karrie and Rubenstein, John L.R. and Madison, Daniel V. and Hallmayer, Joachim and Froehlich-Santino, Wendy M. and Bernstein, Jon A. and Dolmetsch, Ricardo (2016) A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients. eLife, 5 (e13073). pp. 1-26. ISSN 2050-084X

Abstract

Dravet Syndrome is an intractable form of childhood epilepsy associated with deleterious mutations in SCN1A, the gene encoding neuronal sodium channel Nav1.1. Earlier studies using human induced pluripotent stem cells (iPSCs) have produced mixed results regarding the importance of Nav1.1 in human inhibitory versus excitatory neurons. We studied a Nav1.1 mutation (p.S1328P) identified in a pair of twins with Dravet Syndrome and generated iPSC-derived neurons from these patients. Characterization of the mutant channel revealed a decrease in current amplitude and hypersensitivity to steady-state inactivation. We then differentiated Dravet-Syndrome and control iPSCs into telencephalic excitatory neurons or medial ganglionic eminence (MGE)-like inhibitory neurons. Dravet inhibitory neurons showed deficits in sodium currents and action potential firing, which were rescued by a Nav1.1 transgene, whereas Dravet excitatory neurons were normal. Our study identifies biophysical impairments underlying a deleterious Nav1.1 mutation and supports the hypothesis that Dravet Syndrome arises from defective inhibitory neurons.

Item Type: Article
Keywords: Dravet Syndrome, Nav1.1, iPSC, inhibitory interneuron
Date Deposited: 30 Jul 2016 00:45
Last Modified: 30 Jul 2016 00:45
URI: https://oak.novartis.com/id/eprint/23782

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