A channelopathy contributes to cerebellar dysfunction in a model of multiple sclerosis

Authors

  • Shannon D. Shields PhD,

    1. Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT
    2. Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, CT
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  • Xiaoyang Cheng PhD,

    1. Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT
    2. Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, CT
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  • Andreas Gasser PhD,

    1. Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT
    2. Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, CT
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  • Carl Y. Saab PhD,

    1. Department of Surgery, Rhode Island Hospital, Brown Alpert Medical School, Providence, RI
    2. Department of Neuroscience, Brown University, Providence, RI
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  • Lynda Tyrrell MS,

    1. Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT
    2. Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, CT
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  • Emmanuella M. Eastman BS,

    1. Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT
    2. Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, CT
    Current affiliation:
    1. Biotechnology Department, Johns Hopkins University, Baltimore, MD. Current address for Andreas Gasser: Department of Trauma, Hand, and Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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  • Masashi Iwata PhD,

    1. Department of Surgery, Rhode Island Hospital, Brown Alpert Medical School, Providence, RI
    2. Department of Neuroscience, Brown University, Providence, RI
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  • Pamela J. Zwinger BS,

    1. Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT
    2. Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, CT
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  • Joel A. Black PhD,

    1. Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT
    2. Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, CT
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  • Sulayman D. Dib-Hajj PhD,

    1. Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT
    2. Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, CT
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  • Stephen G. Waxman MD, PhD

    Corresponding author
    1. Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT
    2. Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, CT
    • Neuroscience and Regeneration Research Center, Veterans' Affairs Connecticut Healthcare System, 950 Campbell Ave, Bldg 34, West Haven, CT 06516
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Abstract

Objective:

Cerebellar dysfunction in multiple sclerosis (MS) contributes significantly to disability, is relatively refractory to symptomatic therapy, and often progresses despite treatment with disease-modifying agents. We previously observed that sodium channel Nav1.8, whose expression is normally restricted to the peripheral nervous system, is present in cerebellar Purkinje neurons in a mouse model of MS (experimental autoimmune encephalomyelitis [EAE]) and in humans with MS. Here, we tested the hypothesis that upregulation of Nav1.8 in cerebellum in MS and EAE has functional consequences contributing to symptom burden.

Methods:

Electrophysiology and behavioral assessment were performed in a new transgenic mouse model overexpressing Nav1.8 in Purkinje neurons. We also measured EAE symptom progression in mice lacking Nav1.8 compared to wild-type littermates. Finally, we administered the Nav1.8-selective blocker A803467 in the context of previously established EAE to determine reversibility of MS-like deficits.

Results:

We report that, in the context of an otherwise healthy nervous system, ectopic expression of Nav1.8 in Purkinje neurons alters their electrophysiological properties, and disrupts coordinated motor behaviors. Additionally, we show that Nav1.8 expression contributes to symptom development in EAE. Finally, we demonstrate that abnormal patterns of Purkinje neuron firing and MS-like deficits in EAE can be partially reversed by pharmacotherapy using a Nav1.8-selective blocker.

Interpretation:

Our results add to the evidence that a channelopathy contributes to cerebellar dysfunction in MS. Our data suggest that Nav1.8-specific blockers, when available for humans, merit study in MS. Ann Neurol 2012;71:186–194

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