title: A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients.
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.
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, United States.|Department of Neurobiology, Stanford University School of Medicine, Stanford, United States.
authors.forename: Yishan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: 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.
authors.forename: Sergiu P
authors.initials: SP
authors.lastname: Paşca
authors.affiliation: Department of Neurobiology, Stanford University School of Medicine, Stanford, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Portmann
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, United States.|Department of Neurobiology, Stanford University School of Medicine, Stanford, United States.
authors.forename: Carleton
authors.initials: C
authors.lastname: Goold
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, United States.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Worringer
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, United States.
authors.forename: Wendy
authors.initials: W
authors.lastname: Guan
authors.affiliation: Department of Neurobiology, Stanford University School of Medicine, Stanford, United States.
authors.forename: Karen C
authors.initials: KC
authors.lastname: Chan
authors.affiliation: Department of Neurobiology, Stanford University School of Medicine, Stanford, United States.
authors.forename: Hui
authors.initials: H
authors.lastname: Gai
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Vogt
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, United States.
authors.forename: Ying-Jiun J
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Department of Neurobiology, Stanford University School of Medicine, Stanford, United States.
authors.forename: Rong
authors.initials: R
authors.lastname: Mao
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, United States.
authors.forename: Karrie
authors.initials: K
authors.lastname: Chan
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, United States.
authors.forename: John Lr
authors.initials: JL
authors.lastname: Rubenstein
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, United States.
authors.forename: Daniel V
authors.initials: DV
authors.lastname: Madison
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, United States.
authors.forename: Joachim
authors.initials: J
authors.lastname: Hallmayer
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, United States.
authors.forename: Wendy M
authors.initials: WM
authors.lastname: Froehlich-Santino
authors.affiliation: Department of Pediatrics, Division of Genetics, Stanford University School of Medicine, Stanford, United States.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Bernstein
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, United States.|Department of Neurobiology, Stanford University School of Medicine, Stanford, United States.
authors.forename: Ricardo E
authors.identifier: 0000-0002-2738-8338
authors.initials: RE
authors.lastname: Dolmetsch
mesh_terms: D002478:Cells, Cultured; D004831:Epilepsies, Myoclonic / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology; D009154:Mutation; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000172:deficiency*; D009474:Neurons / Q000502:physiology*; D013687:Telencephalon / Q000502:physiology*
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human
keywords: Dravet Syndrome; NaV1.1; SCN1A; human; iPSC; interneurons; neuroscience; rat