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Neurobiol Dis. 2013 Jan;49:200-10. doi: 10.1016/j.nbd.2012.07.019. Epub 2012 Jul 28.

Limited regional cerebellar dysfunction induces focal dystonia in mice.

Author information

1
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
2
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
3
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
4
Department of Human Genetics, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands; Department of Neurology, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands.
5
Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
6
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: ejhess@emory.edu.

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.

KEYWORDS:

Cerebellum; Cre recombinase; Electrical stimulation; Focal dystonia; Lentivirus

PMID:
22850483
PMCID:
PMC3567246
DOI:
10.1016/j.nbd.2012.07.019
[Indexed for MEDLINE]
Free PMC Article

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