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Author Notes:

Correspondence: Andrew Escayg, Ph.D., Emory University, Department of Human Genetics, 615 Michael Street, Whitehead Building, Suite 301, Atlanta, Georgia 30322; Tel number: (404) 712-8328; Fax number: (404) 727-3949; Email: aescayg@genetics.emory.edu

and Alan L. Goldin, M.D./Ph.D., University of California, Irvine, Department of Microbiology and Molecular Genetics, B240 Med Sci I, Irvine, CA 92697; Tel number: (949) 824-5334; Fax number: (949) 824-8504; Email: agoldin@uci.edu

Authors' Contributions: Bin Tang and Karoni Dutt contributed equally

Acknowledgments: We are grateful to Cheryl Strauss for editing this manuscript.


Research Funding:

This study was supported by NIH Research Grants NS046484, NS051834 (A.E.) and NS48336 (A.L.G.), and grants from the March of Dimes Birth Defects Foundation (#5-FY02-250) (A.E.) and the McKnight Endowment Fund for Neuroscience (A.L.G.), the European Integrated Project EPICURE (M.M.) and the Italian Telethon grant GGP07277 (M.M.).

K.D. was supported by a fellowship from the Epilepsy Foundation.

L.P. was supported fellowships from AFIP and FAPESP (07-50534-5).

ST was supported by FAPESP (CEPID#98/14303-3).


  • Sodium channel
  • SCN1A
  • GEFS+
  • SMEI
  • epilepsy
  • mutation

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

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Journal Title:

Neurobiology of Disease


Volume 35, Number 1


, Pages 91-102

Type of Work:

Article | Post-print: After Peer Review


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.

Copyright information:

© 2009 Elsevier Inc. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported License (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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