Physiological and genetic analysis of multiple sodium channel variants in a model of genetic absence epilepsy

MK Oliva; TC McGarr; BJ Beyer; E Gazina; DI Kaplan; L Cordeiro; E Thomas; SD Dib-Hajj; SG Waxman; WN Frankel; S Petrou

Journal article

Physiological and genetic analysis of multiple sodium channel variants in a model of genetic absence epilepsy

MK Oliva, TC McGarr, BJ Beyer, E Gazina, DI Kaplan, L Cordeiro, E Thomas, SD Dib-Hajj, SG Waxman, WN Frankel, S Petrou

NEUROBIOLOGY OF DISEASE | ACADEMIC PRESS INC ELSEVIER SCIENCE | Published : 2014

DOI: 10.1016/j.nbd.2014.03.007

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Abstract

In excitatory neurons, SCN2A (NaV1.2) and SCN8A (NaV1.6) sodium channels are enriched at the axon initial segment. NaV1.6 is implicated in several mouse models of absence epilepsy, including a missense mutation identified in a chemical mutagenesis screen (Scn8a(V929F)). Here, we confirmed the prior suggestion that Scn8a(V929F) exhibits a striking genetic background-dependent difference in phenotypic severity, observing that spike-wave discharge (SWD) incidence and severity are significantly diminished when Scn8a(V929F) is fully placed onto the C57BL/6J strain compared with C3H. Examination of sequence differences in NaV subunits between these two inbred strains suggested NaV1.2(V752F) as a p..

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University of Melbourne Researchers

Steven Petrou Author Florey Department of Neuroscience and Mental Health

Evan Thomas Author Medical Biology (w.e.h.i.)

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Grants

Awarded by NHMRC programme grant

Awarded by NHMRC fellowship

Awarded by NIH

Awarded by NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

Funding Acknowledgements

We thank Verity Letts for help with EEG recordings and advice, and Joanne Smith for animal husbandry. This study was supported by NHMRC programme grant 400121 and NHMRC fellowship 1005050 to SP. The Florey Institute of Neuroscience and Mental Health is supported by Victorian State Government infrastructure funds. WNF and scientific cores at The Jackson Laboratory were supported by grants from the NIH (R01 NS031348, P30 CA034186, respectively). SD-H and SGW are supported by grants from the U.S. Department of Veterans Affairs.