Altered Function of the SCN1A Voltage-gated Sodium Channel Leads to gamma-Aminobutyric Acid-ergic (GABAergic) Interneuron Abnormalities

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dc.contributor.author Martin, Melinda S.
dc.contributor.author Dutt, Karoni
dc.contributor.author Papale, Ligia Assumpção [UNIFESP]
dc.contributor.author Dube, Celine M.
dc.contributor.author Dutton, Stacey B.
dc.contributor.author Haan, Georgius de
dc.contributor.author Shankar, Anupama
dc.contributor.author Tufik, Sergio [UNIFESP]
dc.contributor.author Meisler, Miriam H.
dc.contributor.author Baram, Tallie Z.
dc.contributor.author Goldin, Alan L.
dc.contributor.author Escayg, Andrew
dc.date.accessioned 2016-01-24T13:59:28Z
dc.date.available 2016-01-24T13:59:28Z
dc.date.issued 2010-03-26
dc.identifier http://dx.doi.org/10.1074/jbc.M109.078568
dc.identifier.citation Journal of Biological Chemistry. Bethesda: Amer Soc Biochemistry Molecular Biology Inc, v. 285, n. 13, p. 9823-9834, 2010.
dc.identifier.issn 0021-9258
dc.identifier.uri http://repositorio.unifesp.br/handle/11600/32383
dc.description.abstract Voltage-gated sodium channels are required for the initiation and propagation of action potentials. Mutations in the neuronal voltage-gated sodium channel SCN1A are associated with a growing number of disorders including generalized epilepsy with febrile seizures plus (GEFS+),(7) severe myoclonic epilepsy of infancy, and familial hemiplegic migraine. To gain insight into the effect of SCN1A mutations on neuronal excitability, we introduced the human GEFS+ mutation SCN1A-R1648H into the orthologous mouse gene. Scn1a(RH/RH) mice homozygous for the R1648H mutation exhibit spontaneous generalized seizures and premature death between P16 and P26, whereas Scn1a(RH/+) heterozygous mice exhibit infrequent spontaneous generalized seizures, reduced threshold and accelerated propagation of febrile seizures, and decreased threshold to flurothyl-induced seizures. Inhibitory cortical interneurons from P5-P15 Scn1a(RH/+) and Scn1a(RH/RH) mice demonstrated slower recovery from inactivation, greater use-dependent inactivation, and reduced action potential firing compared with wild-type cells. Excitatory cortical pyramidal neurons were mostly unaffected. These results suggest that this SCN1A mutation predominantly impairs sodium channel activity in interneurons, leading to decreased inhibition. Decreased inhibition may be a common mechanism underlying clinically distinct SCN1A-derived disorders. en
dc.description.sponsorship National Institutes of Health
dc.description.sponsorship McKnight Foundation
dc.description.sponsorship Epilepsy Foundation
dc.description.sponsorship Associacao Fundo de Incentivo a Psico-farmacologia
dc.description.sponsorship Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.format.extent 9823-9834
dc.language.iso eng
dc.publisher Amer Soc Biochemistry Molecular Biology Inc
dc.relation.ispartof Journal of Biological Chemistry
dc.rights Acesso aberto
dc.title Altered Function of the SCN1A Voltage-gated Sodium Channel Leads to gamma-Aminobutyric Acid-ergic (GABAergic) Interneuron Abnormalities en
dc.type Artigo
dc.contributor.institution Univ Calif Irvine
dc.contributor.institution Emory Univ
dc.contributor.institution Universidade Federal de São Paulo (UNIFESP)
dc.contributor.institution Univ Michigan
dc.description.affiliation Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92697 USA
dc.description.affiliation Univ Calif Irvine, Dept Anat & Neurobiol, Irvine, CA 92697 USA
dc.description.affiliation Univ Calif Irvine, Dept Pediat, Irvine, CA 92697 USA
dc.description.affiliation Emory Univ, Dept Human Genet, Atlanta, GA 30322 USA
dc.description.affiliation Universidade Federal de São Paulo, Dept Psychobiol, BR-04024000 São Paulo, Brazil
dc.description.affiliation Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA
dc.description.affiliationUnifesp Universidade Federal de São Paulo, Dept Psychobiol, BR-04024000 São Paulo, Brazil
dc.description.sponsorshipID National Institutes of Health: NS046484
dc.description.sponsorshipID National Institutes of Health: NS051834
dc.description.sponsorshipID National Institutes of Health: NS48336
dc.description.sponsorshipID National Institutes of Health: NS34509
dc.description.sponsorshipID National Institutes of Health: NS35437
dc.description.sponsorshipID McKnight Foundation: 34653
dc.description.sponsorshipID FAPESP: 07/50534-0
dc.identifier.doi 10.1074/jbc.M109.078568
dc.description.source Web of Science
dc.identifier.wos WOS:000276165900054



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