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J Neurophysiol 96: 785-793, 2006. First published May 10, 2006; doi:10.1152/jn.01193.2005
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Impaired Motor Function in Mice With Cell-Specific Knockout of Sodium Channel Scn8a (NaV1.6) in Cerebellar Purkinje Neurons and Granule Cells

Stephen I. Levin1,2, Zayd M. Khaliq3, Teresa K. Aman3, Tina M. Grieco3, Jennifer A. Kearney1, Indira M. Raman3,* and Miriam H. Meisler1,*

1Department of Human Genetics and 2Unit for Laboratory Animal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan, and 3Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois

Submitted 9 November 2005; accepted in final form 5 May 2006

The Scn8a gene encodes the voltage-gated Na channel {alpha} subunit NaV1.6, which is widely expressed throughout the nervous system. Global null mutations that eliminate Scn8a in all cells result in severe motor dysfunction and premature death, precluding analysis of the physiological role of NaV1.6 in different neuronal types. To test the effect of cerebellar NaV1.6 on motor coordination in mice, we used the Cre-lox system to eliminate Scn8a expression exclusively in Purkinje neurons (Purkinje KO) and/or granule neurons (granule KO). Whereas granule KO mice had only minor behavioral defects, adult Purkinje KO mice exhibited ataxia, tremor, and impaired coordination. These disorders were exacerbated in double mutants lacking Scn8a in both Purkinje and granule cells (double KO). In Purkinje cells isolated from adult Purkinje KO and double KO but not granule KO mice, the ratio of resurgent-to-transient tetrodotoxin- (TTX)-sensitive Na current amplitudes decreased from ~15 to ~5%. In cerebellar slices, Purkinje cell spontaneous and maximal firing rates were reduced 10-fold and twofold relative to control in Purkinje KO and double KO but not granule KO mice. Additionally, short-term plasticity of high-frequency parallel fiber EPSCs was altered relative to control in Purkinje KO and double KO but not granule KO mice. These data suggest that the specialized kinetics of Purkinje Na channels depend directly on Scn8a expression. The loss of these channels leads to a decrease in Purkinje cell firing rates as well as a modification of the synaptic properties of afferent parallel fibers, with the ultimate consequence of disrupting motor behavior.

Address for reprint requests and other correspondence: M. H. Meisler, Dept. of Human Genetics, 4909 Buhl Box 0618, University of Michigan, Ann Arbor, MI 48109-0618 (E-mail: meislerm{at}umich.edu)




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