Limited regional cerebellar dysfunction induces focal dystonia in mice

• 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
• Journal Title: Neurobiology of Disease
• Volume: Volume 49, Number 1
• Publisher: Elsevier: 12 months | 2013-01-01, Pages 200-210
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.nbd.2012.07.019
• Subjects: Biology, Neuroscience; Biology, Genetics; Health Sciences, Pharmacology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Neurosciences; Neurosciences & Neurology; Focal dystonia; Cerebellum; Lentivirus; Electrical stimulation; Cre recombinase; BENIGN PAROXYSMAL TORTICOLLIS; EPISODIC ATAXIA TYPE-2; CALCIUM-CHANNEL; CACNA1A GENE; TRANSGENIC MICE; BASAL GANGLIA; WRITERS CRAMP; MUTANT MOUSE; RAT; MUTATION

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.