A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients
Yishan Sun,
Sergiu P Paşca,
Thomas Portmann,
Carleton Goold,
Kathleen A Worringer,
Wendy Guan,
Karen C Chan,
Hui Gai,
Daniel Vogt,
Ying-Jiun J Chen,
Rong Mao,
Karrie Chan,
John LR Rubenstein,
Daniel V Madison,
Joachim Hallmayer,
Wendy M Froehlich-Santino,
Jonathan A Bernstein,
Ricardo E Dolmetsch
Affiliations
Yishan Sun
Novartis Institutes for BioMedical Research, Cambridge, United States; Department of Neurobiology, Stanford University School of Medicine, Stanford, United States
Sergiu P Paşca
Department of Neurobiology, Stanford University School of Medicine, Stanford, United States; Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, United States
Thomas Portmann
Department of Neurobiology, Stanford University School of Medicine, Stanford, United States
Carleton Goold
Novartis Institutes for BioMedical Research, Cambridge, United States; Department of Neurobiology, Stanford University School of Medicine, Stanford, United States
Kathleen A Worringer
Novartis Institutes for BioMedical Research, Cambridge, United States
Wendy Guan
Novartis Institutes for BioMedical Research, Cambridge, United States
Karen C Chan
Department of Neurobiology, Stanford University School of Medicine, Stanford, United States
Hui Gai
Department of Neurobiology, Stanford University School of Medicine, Stanford, United States
Daniel Vogt
Department of Psychiatry, University of California, San Francisco, San Francisco, United States
Ying-Jiun J Chen
Department of Psychiatry, University of California, San Francisco, San Francisco, United States
Rong Mao
Department of Neurobiology, Stanford University School of Medicine, Stanford, United States
Karrie Chan
Novartis Institutes for BioMedical Research, Cambridge, United States
John LR Rubenstein
Department of Psychiatry, University of California, San Francisco, San Francisco, United States
Daniel V Madison
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, United States
Joachim Hallmayer
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, United States
Wendy M Froehlich-Santino
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, United States
Jonathan A Bernstein
Department of Pediatrics, Division of Genetics, Stanford University School of Medicine, Stanford, United States
Novartis Institutes for BioMedical Research, Cambridge, United States; Department of Neurobiology, Stanford University School of Medicine, Stanford, United States
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.
