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

Author 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
Institution Univ Calif Irvine
Emory Univ
Universidade Federal de São Paulo (UNIFESP)
Univ Michigan
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.
Language English
Sponsor 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)
Grant number 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
Date 2010-03-26
Published in Journal of Biological Chemistry. Bethesda: Amer Soc Biochemistry Molecular Biology Inc, v. 285, n. 13, p. 9823-9834, 2010.
ISSN 0021-9258 (Sherpa/Romeo, impact factor)
Publisher Amer Soc Biochemistry Molecular Biology Inc
Extent 9823-9834
Origin http://dx.doi.org/10.1074/jbc.M109.078568
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000276165900054
URI http://repositorio.unifesp.br/handle/11600/32383

Show full item record




File

File Size Format View

There are no files associated with this item.

This item appears in the following Collection(s)

Search


Browse

Statistics

My Account