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The neural substrates of rapid-onset Dystonia-Parkinsonism

Abstract

Although dystonias are a common group of movement disorders, the mechanisms by which brain dysfunction results in dystonia are not understood. Rapid-onset Dystonia-Parkinsonism (RDP) is a hereditary dystonia caused by mutations in the ATP1A3 gene. Affected individuals can be free of symptoms for years, but rapidly develop persistent dystonia and Parkinsonism-like symptoms after a stressful experience. Using a mouse model, we found that an adverse interaction between the cerebellum and basal ganglia can account for the symptoms of these individuals. The primary instigator of dystonia was the cerebellum, whose aberrant activity altered basal ganglia function, which in turn caused dystonia. This adverse interaction between the cerebellum and basal ganglia was mediated through a di-synaptic thalamic pathway that, when severed, alleviated dystonia. Our results provide a unifying hypothesis for the involvement of cerebellum and basal ganglia in the generation of dystonia and suggest therapeutic strategies for the treatment of RDP.

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Figure 1: Chronic partial blockade of basal ganglia sodium pumps induces Parkinsonism-like symptoms.
Figure 2: Chronic partial blockade of cerebellar sodium pumps results in ataxia and dystonic-like postures.
Figure 3: Stress-induced dystonia in mice requires interaction between cerebellar and basal ganglia motor control loops.
Figure 4: Dystonic postures correlate with abnormal cerebellar activity.
Figure 5: Reducing aberrant cerebellar activity or silencing cerebellar output lessens dystonia.
Figure 6: Severing the link between the cerebellum and basal ganglia alleviates dystonia.

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Acknowledgements

We thank the members of the Khodakhah laboratory for invaluable discussions and comments on the manuscript, and for evaluating and scoring motor dysfunction. We also thank D. Purpura, R. Sillitoe and S. Reeber for help and advice. This work was supported by US National Institutes of Health grants NS063227 and NS054251 to K.K. Additional support was provided by an administrative supplement to US National Institutes of Health grant NS058949 (A. Brashear).

Author information

Authors and Affiliations

Authors

Contributions

The studies were initiated by K.K. and D.P.C., who designed the bulk of the experiments and wrote the manuscript. D.P.C. performed all of the experiments except those in Figures 5b,c and 6. R.F. designed and carried out the experiments in Figure 6 and designed and helped F.K. perform the experiments shown in Figures 5b,c. R.F. also contributed to the experiments reported in the Supplementary Information.

Corresponding author

Correspondence to Kamran Khodakhah.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Data 1–5 (PDF 2996 kb)

Supplementary Video 1

Ouabain infusion to the basal ganglia causes parkinsonism (WMV 2679 kb)

Supplementary Video 2

Ouabain infusion to the cerebellum induces dystonia (WMV 2663 kb)

Supplementary Video 3

Ouabain infusion into the cerebellum and basal ganglia induces a mild dyskinesia (WMV 2674 kb)

Supplementary Video 4

Stress induces dystonia in mice with perfusion of ouabain to the cerebellum and basal ganglia (WMV 2679 kb)

Supplementary Video 5

Stress induces a severe and persistent dystonia in mice with perfusion of a high concentration of ouabain to the cerebellum and basal ganglia (WMV 2654 kb)

Supplementary Video 6

Mice with perfusion of ouabain to the basal ganglia alone show no stress induced symptoms (WMV 1741 kb)

Supplementary Video 7

Mice with perfusion of ouabain to the cerebellum alone show no stress induced symptoms (WMV 1758 kb)

Supplementary Video 8

Inactivating the motor cortex does not eliminate dystonia in mice with ouabain infusion to the cerebellum (WMV 2641 kb)

Supplementary Video 9

Reducing aberrant activity in the cerebellum with GABA alleviates dystonia in mice with ouabain infusion to the cerebellum (WMV 1681 kb)

Supplementary Video 10

Lesioning the deep cerebellar nuclei in mice with ouabain infusion to the cerebellum prevents the onset of dystonia (WMV 771 kb)

Supplementary Video 11

Bilaterally lesioning CL thalamus in mice with ouabain infusion to the cerebellum prevents the onset of dystonia (WMV 1650 kb)

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Calderon, D., Fremont, R., Kraenzlin, F. et al. The neural substrates of rapid-onset Dystonia-Parkinsonism. Nat Neurosci 14, 357–365 (2011). https://doi.org/10.1038/nn.2753

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