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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; Telephone number: (404) 712-8328; Fax number: (404) 727-3949; Email: aescayg@emory.edu

Acknowledgments: We would like to thank the laboratory of Dr. William Catterall for assistance with the hyperthermia seizure induction paradigm and guidance with immunohistochemistry.

We are grateful to Cheryl Strauss for editorial assistance.

Subject:

Research Funding:

This study was supported by grants from the NIH (R01 NS072221 to AE, and 1F31 NS065694 to SBD) and by a predoctoral fellowship from the Epilepsy Foundation (SBD).

This research was also supported in part by the NINDS core facilities grant P30N5055077 to the Emory University Microscopy Core.

Keywords:

  • Epilepsy
  • SCN1A
  • ion channels
  • interneurons
  • pyramidal neurons

Preferential inactivation of Scn1a in parvalbumin interneurons increases seizure susceptibility

Journal Title:

Neurobiology of Disease

Volume:

Volume 0

Publisher:

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Voltage-gated sodium channels (VGSCs) are essential for the generation and propagation of action potentials in electrically excitable cells. Dominant mutations in SCN1A, which encodes the Nav1.1 VGSC α-subunit, underlie several forms of epilepsy, including Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+). Electrophysiological analyses of DS and GEFS+ mouse models have led to the hypothesis that SCN1A mutations reduce the excitability of inhibitory cortical and hippocampal interneurons. To more directly examine the relative contribution of inhibitory interneurons and excitatory pyramidal cells to SCN1A-derived epilepsy, we first compared the expression of Nav1.1 in inhibitory parvalbumin (PV) interneurons and excitatory neurons from P22 mice using fluorescent immunohistochemistry. In the hippocampus and neocortex, 69% of Nav1.1 immunoreactive neurons were also positive for PV. In contrast, 13% and 5% of Nav1.1 positive cells in the hippocampus and neocortex, respectively, were found to co-localize with excitatory cells identified by CaMK2α immunoreactivity. Next, we reduced the expression of Scn1a in either a subset of interneurons (mainly PV interneurons) or excitatory cells by crossing mice heterozygous for a floxed Scn1a allele to either the Ppp1r2-Cre or EMX1-Cre transgenic lines, respectively. The inactivation of one Scn1a allele in interneurons of the neocortex and hippocampus was sufficient to reduce thresholds to flurothyl- and hyperthermia-induced seizures, whereas thresholds were unaltered following inactivation in excitatory cells. Reduced interneuron Scn1a expression also resulted in the generation of spontaneous seizures. These findings provide direct evidence for an important role of PV interneurons in the pathogenesis of Scn1a-derived epilepsies.

Copyright information:

© 2012 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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