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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

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

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Autor(es):
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Martin, Melinda S. [1] ; Dutt, Karoni [2] ; Papale, Ligia A. [1, 3] ; Dube, Celine M. [4, 5] ; Dutton, Stacey B. [1] ; de Haan, Georgius [6] ; Shankar, Anupama [1] ; Tufik, Sergio [3] ; Meisler, Miriam H. [6] ; Baram, Tallie Z. [4, 5] ; Goldin, Alan L. [2, 4] ; Escayg, Andrew [1]
Número total de Autores: 12
Afiliação do(s) autor(es):
[1] Emory Univ, Dept Human Genet, Atlanta, GA 30322 - USA
[2] Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92697 - USA
[3] Univ Fed Sao Paulo, Dept Psychobiol, BR-04024000 Sao Paulo - Brazil
[4] Univ Calif Irvine, Dept Anat & Neurobiol, Irvine, CA 92697 - USA
[5] Univ Calif Irvine, Dept Pediat, Irvine, CA 92697 - USA
[6] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 - USA
Número total de Afiliações: 6
Tipo de documento: Artigo Científico
Fonte: Journal of Biological Chemistry; v. 285, n. 13, p. 9823-9834, MAR 26 2010.
Citações Web of Science: 127
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. (AU)

Processo FAPESP: 07/50534-0 - Caracterização do padrão de sono em modelos animais de epilepsia
Beneficiário:Ligia Assumpção Papale
Linha de fomento: Bolsas no Brasil - Doutorado Direto