Cerebellar dysfunction in multiple sclerosis: Evidence for an acquired channelopathy

  • Waxman S
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Abstract

Cerebellar dysfunction in multiple sclerosis (MS) is a significant contributor to disability, is relatively refractory to symptomatic therapy, and often progresses despite treatment with disease-modifying agents. Thus, there is a need for better understanding of its pathophysiology. This chapter reviews a growing body of evidence which suggests that mis-tuning of Purkinje cells, due to expression of an abnormal repertoire of sodium channels, contributes to cerebellar deficits in MS. Within the normal nervous system, sodium channel Nav1.8 is expressed in a highly specific manner within spinal sensory and trigeminal neurons, and is not present within Purkinje cells, Nav1.8 mRNA and protein are, however, expressed within Purkinje cells both in models of MS (experimenal autoimmume encephalomyelitis; EAE), and in postmortem tissue from humans with MS. Expression of Nav1.8 within Purkinje cells in vitro alters electrogenesis in these cells in several ways: first, by increasing duration and amplitude of action potentials; second, by decreasing the proportion of action potentials that are conglomerate and the number of spikes per conglomerate action potential; and third, by supporting sustained, pacemaker-like impulse trains in response to depolarization, which are not seen in the absence of Nav1.8. Similar changes are observed in recordings from Purkinje cells in vivo from mice with EAE. Taken together, these results suggest that expression of Nav1.8 within Purkinje cells distorts their pattern of firing in MS. © 2004 Elsevier Inc.

Author-supplied keywords

  • Purkinje cells
  • acquired channelopathy
  • action potential electrogenesis
  • sodium channels

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Authors

  • Stephen G. Waxman

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