Cerebellar Dysfunction in DYT1

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Abstract DYT1 is a debilitating movement disorder caused by loss-of-function mutations in torsinA. How these mutations cause dystonia remains unknown. Mouse models which have embryonically targeted torsinA have failed to recapitulate the dystonia seen in patients, possibly due to differential developmental compensation between rodents and humans. To address this issue, we have developed a new mouse model where torsinA is acutely knocked down in select brain regions of adult mice using shRNAs. We have found that torsinA knockdown in the cerebellum, but not in the basal ganglia, is sufficient to induce dystonia. Abnormal motor symptoms in dystonic animals were associated with irregular cerebellar output caused by changes in the intrinsic activity of both Purkinje cells and neurons of the deep cerebellar nuclei. This proposal capitalizes on this dystonic model of DYT1 to explore at circuit, neuronal, and molecular levels how loss of torsinA causes dystonia. The proposal is based on three specific aims. In the first specific aim we will test the hypothesis that in DYT1 abnormal cerebellar output causes dystonia by altering the activity of the basal ganglia via the thalamic disynaptic Cb-BG pathway that we have characterized. Specific Aim 2 will test the hypothesis that selective knock down of torsinA in cerebellar Purkinje cells and/or DCN neurons causes cerebellar dysfunction and dystonia. And lastly the third specific Aim tests the hypothesis that knock down of torsinA alters the intrinsic pacemaking of Purkinje cells and DCN neurons by altering the expression or function of select conductances. Successful accomplishment of the aims set will significantly advance our understanding of DYT1 dystonia, and may provide valuable potential therapeutic targets for its treatment.