A BAC transgenic mouse model reveals neuron subtype-specific effects of a Generalized Epilepsy with Febrile Seizures Plus (GEFS plus ) mutation

Autor(es):Mostrar menos -

Tang, Bin ^[1] ; Dutt, Karoni ^[2] ; Papale, Ligia ^{[3, 1]} ; Rusconi, Raffaella ^[4] ; Shankar, Anupama ^[1] ; Hunter, Jessica ^[1] ; Tufik, Sergio ^[3] ; Yu, Frank H. ^[5] ; Catterall, William A. ^[5] ; Mantegazza, Massimo ^{[4, 6]} ; Goldin, Alan L. ^{[2, 7]} ; Escayg, Andrew ^[1]

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, Sao Paulo - Brazil

^[4] Ist Neurolog Besta, Dept Neurophysiopathol, I-20133 Milan - Italy

^[5] Univ Washington, Dept Pharmacol, Seattle, WA 98195 - USA

^[6] Equipe AVENIR, IFR 95 Paris 5, F-75006 Paris - France

^[7] Univ Calif Irvine, Dept Anat & Neurobiol, Irvine, CA 92697 - USA

• Tipo de documento: Artigo Científico
• Fonte: Neurobiology of Disease; v. 35, n. 1, p. 91-102, JUL 2009.
• Citações Web of Science: 68

Resumo

Mutations in the voltage-gated sodium channel SCN1A are responsible for a number of seizure disorders including Generalized Epilepsy with Febrile Seizures Plus (GEFS+) and Severe Myoclonic Epilepsy of Infancy (SMEI). To determine the effects of SCN1A mutations on channel function in vivo, we generated a bacterial artificial chromosome (BAC) transgenic mouse model that expresses the human SCN1A GEFS+ mutation, R1648H. Mice with the R1648H mutation exhibit a more severe response to the proconvulsant kainic acid compared with mice expressing a control Scn1a transgene. Electrophysiological analysis of dissociated neurons from mice with the R1648H mutation reveal delayed recovery from inactivation and increased use-dependent inactivation only in inhibitory bipolar neurons, as well as a hyperpolarizing shift in the voltage dependence of inactivation only in excitatory pyramidal neurons. These results demonstrate that the effects of SCN1A mutations are cell type-dependent and that the R1648H mutation specifically leads to a reduction in interneuron excitability. (C) 2009 Elsevier Inc. All rights reserved. (AU)

• Processo FAPESP: 98/14303-3 - Center for Sleep Studies
• Beneficiário: Sergio Tufik
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs