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Author Notes:

To whom correspondence should be addressed: Andrew Escayg, Department of Human Genetics, Emory University, 615 Michael Street, Whitehead Building, Suite 301, Atlanta, GA, 30322, USA, Tel.: (404) 712-8328; Fax: (404) 727-3949; Email: aescayg@emory.edu

OR Alan Goldin, Department of Microbiology and Molecular Genetics and Anatomy and Neurobiology, University of California, Irvine, CA 92697-4025, USA, Tel.: (949) 824-5334; Fax: (949)-824-8504, Email: agoldin@uci.edu

We would like to thank Dr. David Weinshenker and Dr. Jason Schroeder of the Emory University Rodent Behavioral Core for assistance with assessing locomotor activity.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Subjects:

Research Funding:

Research in this publication was supported by the National Institute of Neurological Disorders and Stroke (NINDS) and National Institute on Deafness and Communication Disorders (NIDCD) of the National Institutes of Health (NIH) under award numbers R01NS072221 (A.E.), R01NS048336 (A.L.G.), R01NS065187 (A.E. and A.L.G.), F31NS074717 (C.D.M), and R01DC008343 (R.L).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • Na(v)1.6
  • Na(v)1.1
  • Audiogenic seizure
  • Voltage sensor
  • Sodium channel
  • GEFS
  • Dravet syndrome
  • Interneuron
  • SODIUM-CHANNEL SCN8A
  • SEVERE MYOCLONIC EPILEPSY
  • DE-NOVO MUTATIONS
  • INDUCE C-FOS
  • AUDIOGENIC-SEIZURES
  • MOUSE MODEL
  • MICE
  • ENCEPHALOPATHY
  • NA(V)1.6
  • GENE

An Scn1a epilepsy mutation in Scn8a alters seizure susceptibility and behavior

Tools:

Journal Title:

Experimental Neurology

Volume:

Volume 275

Publisher:

, Pages 46-58

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Understanding the role of SCN8A in epilepsy and behavior is critical in light of recently identified human SCN8A epilepsy mutations. We have previously demonstrated that Scn8amed and Scn8amed-jo mice carrying mutations in the Scn8a gene display increased resistance to flurothyl and kainic acid-induced seizures; however, they also exhibit spontaneous absence seizures. To further investigate the relationship between altered SCN8A function and epilepsy, we introduced the SCN1A-R1648H mutation, identified in a family with generalized epilepsy with febrile seizures plus (GEFS+), into the corresponding position (R1627H) of the mouse Scn8a gene. Heterozygous R1627H mice exhibited increased resistance to some forms of pharmacologically and electrically induced seizures and the mutant Scn8a allele ameliorated the phenotype of Scn1a-R1648H mutants. Hippocampal slices from heterozygous R1627H mice displayed decreased bursting behavior compared to wild-type littermates. Paradoxically, at the homozygous level, R1627H mice did not display increased seizure resistance and were susceptible to audiogenic seizures. We furthermore observed increased hippocampal pyramidal cell excitability in heterozygous and homozygous Scn8a-R1627H mutants, and decreased interneuron excitability in heterozygous Scn8a-R1627H mutants. These results expand the phenotypes associated with disruption of the Scn8a gene and demonstrate that an Scn8a mutation can both confer seizure protection and increase seizure susceptibility.

Copyright information:

© 2015 Elsevier Inc.

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