Limited regional cerebellar dysfunction induces focal dystonia in mice

• Type of Material: Article
• Authors: Robert S. Raike, Emory University; Carolyn Pizoli, Johns Hopkins University; Catherine Weisz, Johns Hopkins University; Arn M J. M. van den Maagdenberg, Leiden University; Hyder A Jinnah, Emory University; Ellen Hess, Emory University
• Language: English
• Date: 2013-01-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.nbd.2012.07.019
• Title of Journal or Parent Work: Neurobiology of Disease
• ISSN: 0969-9961
• Volume: 49
• Issue: 1
• Start Page: 200
• End Page: 210
• Grant/Funding Information: This work was supported by United States National Institutes of Health (R01 NS33592, R01 NS40470 and the Emory Core Facilities grant, P30 NS055077), the Dystonia Medical Research Foundation and Tyler's Hope for a Dystonia Cure Foundation.
• Keywords: CACNA1A GENE; Neurosciences; BENIGN PAROXYSMAL TORTICOLLIS; MUTANT MOUSE; BASAL GANGLIA; Life Sciences & Biomedicine; TRANSGENIC MICE; Cerebellum; Lentivirus; MUTATION; WRITERS CRAMP; Science & Technology; EPISODIC ATAXIA TYPE-2; RAT; Electrical stimulation; CALCIUM-CHANNEL; Cre recombinase; Focal dystonia; Neurosciences & Neurology
• Research Categories: Biology, Genetics; Health Sciences, Pharmacology; Biology, Neuroscience

Abstract

Dystonia is a complex neurological syndrome broadly characterized by involuntary twisting movements and abnormal postures. The anatomical distribution of the motor symptoms varies among dystonic patients and can range from focal, involving an isolated part of the body, to generalized, involving many body parts. Functional imaging studies of both focal and generalized dystonias in humans often implicate the cerebellum suggesting that similar pathological processes may underlie both. To test this, we exploited tools developed in mice to generate animals with gradients of cerebellar dysfunction. By using conditional genetics to regionally limit cerebellar dysfunction, we found that abnormalities restricted to Purkinje cells were sufficient to cause dystonia. In fact, the extent of cerebellar dysfunction determined the extent of abnormal movements. Dysfunction of the entire cerebellum caused abnormal postures of many body parts, resembling generalized dystonia. More limited regions of dysfunction that were created by electrical stimulation or conditional genetic manipulations produced abnormal movements in an isolated body part, resembling focal dystonia. Overall, these results suggest that focal and generalized dystonias may arise through similar mechanisms and therefore may be approached with similar therapeutic strategies.