Nature Neuroscience
- 9, 1142 - 1149 (2006)
Published online: 20 August 2006; Corrected online: 13 December 2006 | doi:10.1038/nn1754
There is an Erratum (January 2007) associated with this Article.
Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancyFrank H Yu1, Massimo Mantegazza1, 4, Ruth E Westenbroek1, Carol A Robbins2, 3, Franck Kalume1, Kimberly A Burton1, William J Spain3, G Stanley McKnight1, Todd Scheuer1 & William A Catterall11
Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280, USA. 2
Department of Neurological Surgery, University of Washington, Seattle, Washington 98195-7280, USA. 3
Department of Neurology, University of Washington, Seattle, Washington 98195-7280, USA. 4
Department of Neurophysiology, Instituto Neurologico Besta, via Temolo 4, 20126 Milano, Italy.
Correspondence should be addressed to William A Catterall wcatt@u.washington.edu 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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