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

Bin Tang; Karoni Dutt; Ligia Papale; Raffaella Rusconi; Anupama Shankar; Jessica Hunter; Sergio Tufik; Frank H. Yu; William A. Catterall; Massimo Mantegazza; Alan L. Goldin; Andrew Escayg

Neurobiology of Disease (Jul 2009)

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

Bin Tang,
Karoni Dutt,
Ligia Papale,
Raffaella Rusconi,
Anupama Shankar,
Jessica Hunter,
Sergio Tufik,
Frank H. Yu,
William A. Catterall,
Massimo Mantegazza,
Alan L. Goldin,
Andrew Escayg

Affiliations

Bin Tang: Department of Human Genetics, Emory University, Atlanta, GA 30322, USA
Karoni Dutt: Department of Microbiology and Molecular Genetics, University of California, Irvine, CA 92697, USA
Ligia Papale: Department of Human Genetics, Emory University, Atlanta, GA 30322, USA; Department of Psychobiology, Universidade Federal de São Paulo, São Paulo, Brazil
Raffaella Rusconi: Department of Neurophysiopathology, Istituto Neurologico Besta, 20133 Milano, Italy
Anupama Shankar: Department of Human Genetics, Emory University, Atlanta, GA 30322, USA
Jessica Hunter: Department of Human Genetics, Emory University, Atlanta, GA 30322, USA
Sergio Tufik: Department of Psychobiology, Universidade Federal de São Paulo, São Paulo, Brazil
Frank H. Yu: Department of Pharmacology, University of Washington, Seattle, WA 98195, USA
William A. Catterall: Department of Pharmacology, University of Washington, Seattle, WA 98195, USA
Massimo Mantegazza: Department of Neurophysiopathology, Istituto Neurologico Besta, 20133 Milano, Italy; Equipe AVENIR, IFR 95 – Paris V, 75006 Paris, France
Alan L. Goldin: Department of Microbiology and Molecular Genetics, University of California, Irvine, CA 92697, USA; Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697, USA; Corresponding authors. Andrew Escayg is to be contacted at the Department of Human Genetics, Emory University, 615 Michael Street, Whitehead Building, Suite 301, Atlanta, GA 30322, USA, Fax: +1 404 727-3949. Alan L. Goldin, Department of Microbiology and Molecular Genetics, University of California, Irvine, B240 Med Sci I, Irvine, CA 92697, USA. Fax: +1 949 824-8504.
Andrew Escayg: Department of Human Genetics, Emory University, Atlanta, GA 30322, USA; Corresponding authors. Andrew Escayg is to be contacted at the Department of Human Genetics, Emory University, 615 Michael Street, Whitehead Building, Suite 301, Atlanta, GA 30322, USA, Fax: +1 404 727-3949. Alan L. Goldin, Department of Microbiology and Molecular Genetics, University of California, Irvine, B240 Med Sci I, Irvine, CA 92697, USA. Fax: +1 949 824-8504.

Journal volume & issue: Vol. 35, no. 1
pp. 91 – 102

Abstract

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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.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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