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Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy

An Erratum to this article was published on 01 January 2007

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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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Figure 1: Targeting construct and generation of NaV1.1 null mice.
Figure 2: Premature deaths of NaV1.1 mutant mice.
Figure 3: Spontaneous epileptic seizures in NaV1.1 heterozygous mice.
Figure 4: Sodium currents from hippocampal neurons in wild-type and heterozygous and null NaV1.1 mice.
Figure 5: Depolarization-evoked firing activity of hippocampal interneurons from NaV1.1 mutant mice.
Figure 6: Upregulation of NaV1.3 channels in the hippocampus of NaV1.1 mutant mice.
Figure 7: Upregulation of NaV1.3 in GABAergic inhibitory interneurons.

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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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Correspondence to William A Catterall.

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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)

Supplementary Note (PDF 100 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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