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

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

Autor Martin, Melinda S. Google Scholar
Dutt, Karoni Google Scholar
Papale, Ligia Assumpção Autor UNIFESP Google Scholar
Dube, Celine M. Google Scholar
Dutton, Stacey B. Google Scholar
Haan, Georgius de Google Scholar
Shankar, Anupama Google Scholar
Tufik, Sergio Autor UNIFESP Google Scholar
Meisler, Miriam H. Google Scholar
Baram, Tallie Z. Google Scholar
Goldin, Alan L. Google Scholar
Escayg, Andrew Google Scholar
Instituição Univ Calif Irvine
Emory Univ
Universidade Federal de São Paulo (UNIFESP)
Univ Michigan
Resumo 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.
Idioma Inglês
Financiador National Institutes of Health
McKnight Foundation
Epilepsy Foundation
Associacao Fundo de Incentivo a Psico-farmacologia
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Número do financiamento National Institutes of Health: NS046484
National Institutes of Health: NS051834
National Institutes of Health: NS48336
National Institutes of Health: NS34509
National Institutes of Health: NS35437
McKnight Foundation: 34653
FAPESP: 07/50534-0
Data de publicação 2010-03-26
Publicado em Journal of Biological Chemistry. Bethesda: Amer Soc Biochemistry Molecular Biology Inc, v. 285, n. 13, p. 9823-9834, 2010.
ISSN 0021-9258 (Sherpa/Romeo, fator de impacto)
Publicador Amer Soc Biochemistry Molecular Biology Inc
Extensão 9823-9834
Fonte http://dx.doi.org/10.1074/jbc.M109.078568
Direito de acesso Acesso aberto Open Access
Tipo Artigo
Web of Science WOS:000276165900054
Endereço permanente http://repositorio.unifesp.br/handle/11600/32383

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