A channelopathy contributes to cerebellar dysfunction in a model of multiple sclerosis
Autor: | Carl Y. Saab, Xiaoyang Cheng, Andreas Gasser, Masashi Iwata, Shannon D. Shields, Stephen G. Waxman, Joel A. Black, Emmanuella M. Eastman, Lynda Tyrrell, Sulayman D. Dib-Hajj, Pamela J. Zwinger |
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Rok vydání: | 2012 |
Předmět: |
Nervous system
Cerebellum Encephalomyelitis Autoimmune Experimental Multiple Sclerosis Mice Transgenic Context (language use) Sodium Channels NAV1.8 Voltage-Gated Sodium Channel Mice Purkinje Cells Channelopathy Cerebellar Diseases medicine Animals Furans Aniline Compounds Multiple sclerosis Experimental autoimmune encephalomyelitis medicine.disease Up-Regulation Disease Models Animal medicine.anatomical_structure Neurology Peripheral nervous system Channelopathies Ectopic expression Neurology (clinical) Psychology Neuroscience Sodium Channel Blockers |
Zdroj: | Annals of Neurology. 71:186-194 |
ISSN: | 0364-5134 |
Popis: | 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 |
Databáze: | OpenAIRE |
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