Mutations in a gene coding for e-sarcoglycan (SGCE in human and Sgce in mouse) have been implicated in myoclonic dystonia, an autosomal dominant movement disorder with incomplete penetrance. However, the function of Sgce and how its mutated forms cause myclonus-dystonia are unknown. Furthermore, specific brain regions and synaptic connections affected in the patients are not identified. These unknowns hamper efforts to adequately understand the pathophysiology of myclonus-dystonia, thus preventing the development of effective therapeutic strategies for patients. A mouse model with similar Sgce mutation is highly desirable and should provide a unique and advantageous opportunity for clarifying the functional role of Sgce in vivo and the pathophysiological roles of SGCE mutations. Furthermore, a mouse model could also be used for screening or developing therapeutics. The broad, long-term objective of our research is to understand how the mutations of Sgce lead to myoclonus dystonia. We hypothesize that Sgce mutations lead to the dysfunction of the basal ganglia circuitry, especially the corticostriatal circuit. We further hypothesize that the mutation of SGCE in the cortex and striatum may alter synaptic transmission and plasticity, ultimately affecting motor control and posture. We plan to test our hypothesis with the following Specific Aims: 1. We will determine the behavioral changes in movement control and posture in the Sgce null mice. These analyses will reveal motor deficits associated with Sgce mutation and reveal functional roles of e-sarcoglycan in motor development and control. 2. We will determine the neural circuits that are involved in the pathogenesis for myoclonus-dystonia using cre-loxP mediated recombination in mice. The results obtained will pave the way for the future electrophysiological and cellular studies to uncover the pathological changes that underlie the disease. The successful completion of the proposed work will advance the understanding of the function of Sgce in vivo and how its mutations lead to myoclonus-dystonia. ? ?
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