title: A channelopathy contributes to cerebellar dysfunction in a model of multiple sclerosis.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Shannon D
authors.initials: SD
authors.lastname: Shields
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Cheng
authors.forename: Andreas
authors.initials: A
authors.lastname: Gasser
authors.forename: Carl Y
authors.initials: CY
authors.lastname: Saab
authors.forename: Lynda
authors.initials: L
authors.lastname: Tyrrell
authors.forename: Emmanuella M
authors.initials: EM
authors.lastname: Eastman
authors.forename: Masashi
authors.initials: M
authors.lastname: Iwata
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Zwinger
authors.forename: Joel A
authors.initials: JA
authors.lastname: Black
authors.forename: Sulayman D
authors.initials: SD
authors.lastname: Dib-Hajj
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D000814:Aniline Compounds / Q000627:therapeutic use; D000818:Animals; D002526:Cerebellar Diseases / Q000235:genetics / Q000503:physiopathology*; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D053447:Channelopathies / Q000235:genetics / Q000503:physiopathology*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000503:physiopathology*; D005663:Furans / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000235:genetics / Q000503:physiopathology*; D062559:NAV1.8 Voltage-Gated Sodium Channel; D011689:Purkinje Cells / Q000473:pathology / Q000502:physiology; D026941:Sodium Channel Blockers / Q000627:therapeutic use; D015222:Sodium Channels / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: C520740:A 803467; D000814:Aniline Compounds; D005663:Furans; D062559:NAV1.8 Voltage-Gated Sodium Channel; C568317:SCN10A protein, human; C568318:Scn10a protein, mouse; D026941:Sodium Channel Blockers; D015222:Sodium Channels