Dystonia is a common neurological disorder broadly characterized by sustained simultaneous contractions of agonist and antagonist muscles. The general goal of our research is to understand the pathophysiology of dystonia. While the focus of dystonia research has been on the basal ganglia, the massive convergence of information required to orchestrate the firing of motoneurons suggests that abnormalities in other motor systems, including the cerebellum, could result in such distorted signaling. Given that lesions of the basal ganglia are identified in some dystonic patients while abnormal activity is observed in the cerebellum of other patients, our experimental approach incorporates the concept that many different brain regions contribute to the expression of dystonia. To understand the pathophysiology principles of dystonia, we have developed 3 mouse models of generalized dystonia in the last funding cycle. These models include the tottering mouse mutant, dystonia induced by the L-type calcium channel agonists and dystonia induced by microinjection of low dose kainate in the cerebellum. With the initial characterization of these models complete, we are poised to determine the anatomical, neurochemical and physiological substrates of dystonia. Our strategy is to test several models of dystonia to identify general pathophysiological principles.
The specific aims are: 1) To determine the anatomical substrates of dystonia by examining the effects of lesions. 2) To identify the neurochemical substrates of dystonia using drug challenge. 3) To characterize Purkinje cell firing patterns in dystonia using multielectrode recording in dystonia. 4) To determine the electromyographic (EMG) correlates of dystonia in the mouse models. The experiments in this proposal apply anatomical, physiological and behavioral techniques to determine the neurobiology of dystonia. Unlike Parkinson disease or Huntington disease where cell death provides clues to the pathogenesis of the movement disorder, dystonia is a functional movement disorder with no obvious markers to help define pathophysiology. With the development of 3 different mouse models of dystonia, we are in an excellent position to examine pathophysiology and provide insight into human disease. Public health relevance: Dystonia is the third most common movement disorder, but current therapies are largely unsatisfactory. The goal is to understand the pathophysiology of dystonia to direct novel treatments.
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