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Cited by 139Ion channel regulation and functionNeuroscience and Neuropharmacology ResearchCardiac electrophysiology and arrhythmias

Impaired Motor Function in Mice With Cell-Specific Knockout of Sodium Channel Scn8a (Na V 1.6) in Cerebellar Purkinje Neurons and Granule Cells

Levin, Stephen I., Khaliq, Zayd M., Aman, Teresa K., Grieco, Tina M., Kearney, Jennifer A., Raman, Indira M., Meisler, Miriam H.·2006·Journal of Neurophysiology
DOI 10.1152/jn.01193.2005
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Abstract

The Scn8a gene encodes the voltage-gated Na channel α subunit Na V 1.6, 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 Na V 1.6 in different neuronal types. To test the effect of cerebellar Na V 1.6 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.

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  • The pace-making defect in L7-DKO mice resembles that of mice lacking the voltage-gated sodium channel subunit Scn8a.

    “The pace-making defect in the L7-DKO mice is highly reminiscent of mice lacking the voltage-gated sodium channel subunit Scn8a (REFS 141–143).”

    From The neurogenetics of alternative splicing (2016) · cites this paper as [143]

  • Nav1.6 functions in part to maintain a resurgent sodium current that enables regular, spontaneous firing.

    “Nav1.6 functions, in part, to maintain a resurgent sodium current that enables regular, spontaneous firing.”

    From The neurogenetics of alternative splicing (2016) · cites this paper as [143]

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Authors
Levin, S. I., Khaliq, Z. M., Aman, T. K., Grieco, T. M., Kearney, J. A., Raman, I. M., & Meisler, M. H.
Affiliations
  • University of Michigan (US)
  • Northwestern University (US)
ORCID
Venue
Journal of Neurophysiology
Publisher
American Physiological Society
Published
2006-08
Volume
96
Issue
2
Pages
785-793
ISSN
  • 0022-3077 (ISSN-L)
  • 1522-1598
DOI
10.1152/jn.01193.2005
OpenAlex
W1996902826
Cited by
138
References
52
Citations by year
2026: 3 · 2025: 8 · 2024: 4 · 2023: 12 · 2022: 3 · 2021: 6 · 2020: 4 · 2019: 7 · 2018: 8 · 2017: 5 · 2016: 4 · 2015: 3 · 2014: 6 · 2013: 10 · 2012: 9
FWCI
4.22
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of Neurophysiology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institute of Neurological Disorders and Stroke (NS-39395, NS 34509, R01NS034509)
  • National Center for Research Resources (T32 RR07008, T32RR007008)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
Keywords
SCN8A, Nav1.6, voltage-gated sodium channels, Purkinje cells, granule cells, motor coordination, ataxia, tetrodotoxin-sensitive sodium current, short-term plasticity, cerebellar development
MeSH terms
Action Potentials, Alleles, Animals, Ataxia, Cerebellum, Cytoplasmic Granules, Electrophysiology, Exons, Mutation, Nerve Fibers, Nerve Tissue Proteins, Neuronal Plasticity, Psychomotor Performance, Purkinje Cells, Synapses, Blotting, Southern, Sodium Channels, Mice, Knockout, Excitatory Postsynaptic Potentials, Reverse Transcriptase Polymerase Chain Reaction, Mice, NAV1.6 Voltage-Gated Sodium Channel

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