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

被引：76

作者：

Tang, Bin ^{[1
]}

Dutt, Karoni ^{[2
]}

Papale, Ligia ^{[1
,4
]}

Rusconi, Raffaella ^{[5
]}

Shankar, Anupama ^{[1
]}

Hunter, Jessica ^{[1
]}

Tufik, Sergio ^{[4
]}

Yu, Frank H. ^{[7
]}

Catterall, William A. ^{[7
]}

Mantegazza, Massimo ^{[5
,6
]}

Goldin, Alan L. ^{[2
,3
]}

Escayg, Andrew ^{[1
]}

机构：

[1] Emory Univ, Dept Human Genet, Atlanta, GA 30322 USA

[2] Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92697 USA

[3] Univ Calif Irvine, Dept Anat & Neurobiol, Irvine, CA 92697 USA

[4] Univ Fed Sao Paulo, Dept Psychobiol, Sao Paulo, Brazil

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

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

[7] Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA

来源：

NEUROBIOLOGY OF DISEASE | 2009年 / 35卷 / 01期

基金：

巴西圣保罗研究基金会;

关键词：

Sodium channel; SCN1A; GEFS; SMEI; Epilepsy; Mutation; SEVERE MYOCLONIC EPILEPSY; CHANNEL ALPHA-SUBUNIT; REDUCED SODIUM CURRENT; MESSENGER-RNAS; ALPHA-1-SUBUNIT MUTATIONS; HIPPOCAMPAL-NEURONS; MISSENSE MUTATION; SCN1A; NA(V)1.1; IDENTIFICATION;

D O I：

10.1016/j.nbd.2009.04.007

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：91 / 102

页数：12

共 42 条

[1] A sodium channel mutation causing epilepsy in man exhibits subtle defects in fast inactivation and activation in vitro [J].