EXCEED THE SPACE PROVIDED. Dystonia is a relatively common neurological disorder broadly characterized by sustained simultaneous contractions of agonist and antagonist muscles. Though clinicopathologic correlation studies in humans have traditionally implicated dysfunctionof the basal ganglia as a source of dystonia, more recent functional studies in humans and extensive work in animal models have consistently implicated the cerebellum as well. The general goal of this research is to understand the pathophysiology of dystonia in mice carrying defined mutations in calcium channel genes. Tottering and leaner mice exhibit dystonia as a consequence of mutations in the calcium channel cc,A subunit gene which encodes the pore-forming protein of P/Q-type voltage-dependent calcium channel. Dystonic episodes in these mice are associated with activation of the cerebellum and cerebellar relay nuclei. The cerebellum is also the site of prominent changes in calcium channel expression. L-type calcium channels are specifically upregulated in this region and treatment with L-type calcium channel antagonists prevents the dystonia. These data suggest that L-type calcium channels may contribute to the generation of the dystonia in these mice. We hypothesize that aberrant calcium channel regulation and abnormal cerebellar function plays an important role in the expression of dystonia in these mice. The proposed experiments therefore focus on calcium channel regulation and the cerebellum to isolate the events giving rise to dystonia.
The specific aims of this proposal are: 1) To assess the role of the cerebellum in dystonia in tottering and leaner mice. 2) To recapitulate dystonic events in wild type mice. 3) To determine the ontogeny of dystonia in tottering mice. 4) To identify the neurochemical effects of P/Q-type calcium channel defects in tottering mice. Tottering and leaner mouse mutants provide a model to study the contributions of a single known gene to the pathophysiology of dystonia. This model provides a unique opportunity to correlate calcium channel regulation with a behavioral outcome to provide insight into the etiology and neurobiologic mechanisms involved in dystonia. PERFORMANCE SITE ========================================Section End===========================================
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