A channelopathy contributes to cerebellar dysfunction in a model of multiple sclerosis
Article first published online: 24 FEB 2012
Copyright © 2012 American Neurological Association
Annals of Neurology
Volume 71, Issue 2, pages 186–194, February 2012
How to Cite
Shields, S. D., Cheng, X., Gasser, A., Saab, C. Y., Tyrrell, L., Eastman, E. M., Iwata, M., Zwinger, P. J., Black, J. A., Dib-Hajj, S. D. and Waxman, S. G. (2012), A channelopathy contributes to cerebellar dysfunction in a model of multiple sclerosis. Ann Neurol., 71: 186–194. doi: 10.1002/ana.22665
- Issue published online: 24 FEB 2012
- Article first published online: 24 FEB 2012
- Accepted manuscript online: 2 NOV 2011 03:51AM EST
- Manuscript Accepted: 24 OCT 2011
- Manuscript Revised: 11 OCT 2011
- Manuscript Received: 28 JUN 2011
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.
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.
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.
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