Abstract
Voltage-gated sodium channels (NaV) are critical for initiation of action potentials. Heterozygous loss-of-function mutations in NaV1.1 channels cause severe myoclonic epilepsy in infancy (SMEI). Homozygous null Scn1a−/− mice developed ataxia and died on postnatal day (P) 15 but could be sustained to P17.5 with manual feeding. Heterozygous Scn1a+/− mice had spontaneous seizures and sporadic deaths beginning after P21, with a notable dependence on genetic background. Loss of NaV1.1 did not change voltage-dependent activation or inactivation of sodium channels in hippocampal neurons. The sodium current density was, however, substantially reduced in inhibitory interneurons of Scn1a+/− and Scn1a−/− mice but not in their excitatory pyramidal neurons. An immunocytochemical survey also showed a specific upregulation of NaV1.3 channels in a subset of hippocampal interneurons. Our results indicate that reduced sodium currents in GABAergic inhibitory interneurons in Scn1a+/− heterozygotes may cause the hyperexcitability that leads to epilepsy in patients with SMEI.
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Change history
13 December 2006
In the version of this article initially published, the acceptance date was incorrect. The paper was accepted on 2 August 2006. This error has been corrected in the PDF versions of the article.
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Acknowledgements
This work was supported by US National Institutes of Health Research Grants (W.A.C., T.S., G.S.M.), a Veteran's Administration Merit Review Grant (W.J.S), a grant from the McKnight Foundation (W.A.C.) and a Canadian Institutes of Health Research fellowship (F.H.Y.).
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Supplementary information
Supplementary Figs. 1
Distribution of NaV1.2 and NaV1.6 in the hippocampus of P14 wild-type(+/+) and knockout (−/−) NaV1.1 mice. (PDF 1125 kb)
Supplementary Fig. 2
Localization of NaV1.2, NaV1.3, and NaV1.6 in dorsal cortex layers II – III of wild-type (+/+) and knockout (−/−) NaV1.1 mice. (PDF 1435 kb)
Supplementary Fig. 3
Localization of NaV1.2, NaV1.3 and NaV1.6 in layers IV – VI of the dorsal cortex. (PDF 1301 kb)
Supplementary Fig. 4
Expression of NaV1.2, NaV1.3, and NaV1.6 channels in the thalamus at the level of the reticular nucleus, in wild-type (+/+) and knockout (−/−) NaV1.1 mice. (PDF 2557 kb)
Supplementary Fig. 5
Distribution of NaV1.2, NaV1.3, and NaV1.6 channels in the cerebellum of wild-type (+/+) and knockout (−/−) NaV1.1 mice. (PDF 1293 kb)
Supplementary Table 1
Action potential parameters from hippocampal interneurons. (PDF 56 kb)
Supplementary Video 1
Spontaneous Seizure in an Scn1a+/− Mouse. (MOV 892 kb)
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Yu, F., Mantegazza, M., Westenbroek, R. et al. Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nat Neurosci 9, 1142–1149 (2006). https://doi.org/10.1038/nn1754
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DOI: https://doi.org/10.1038/nn1754
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