Journal
BRAIN RESEARCH BULLETIN
Volume 165, Issue -, Pages 14-22Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.brainresbull.2020.09.011
Keywords
DYT1 dystonia; Purkinje cell; Patch-clamp recording; Cerebellum; BK channel
Categories
Funding
- Tyler's Hope for a Dystonia Cure, Inc.
- National Institutes of Health [NS54246, NS72872, NS74423, NS75012, NS82244, NS118397]
- Bachmann-Strauss Dystonia & Parkinson Foundation Inc.
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DYT1 dystonia is an inherited movement disorder caused by a heterozygous trinucleotide (GAG) deletion in DYT1/TOR1A, coding for torsinA. Growing evidence suggests that the cerebellum plays a role in the pathogenesis of dystonia. Brain imaging of both DYT1 dystonia patients and animal models show abnormal activity in the cerebellum. The cerebellum-specific knockdown of torsinA in adult mice leads to dystonia-like behavior. Dyt1 Delta GAG heterozygous knock-in mouse model exhibits impaired corticostriatal long-term depression, abnormal muscle co-contraction, and motor deficits. We and others previously reported altered dendritic structures in Purkinje cells in Dyt1 knock-in mouse models. However, whether there are any electrophysiological alterations of the Purkinje cells in Dyt1 knock-in mice is not known. We used the patch-clamp recording in brain slices and in acutely dissociated Purkinje cells to identify specific alterations of Purkinje cells firing. We found abnormal firing of non-tonic type of Purkinje cells in the Dyt1 knock-in mice. Furthermore, the large-conductance calciumactivated potassium (BK) current and the BK channel protein levels were significantly increased in the Dyt1 knock-in mice. Our results support a role of the cerebellum in the pathogenesis of DYT1 dystonia. Manipulating the Purkinje cell firing and cerebellar output may show great promise for treating DYT1 dystonia.
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