Cerebellar Neuromodulation

DESCRIPTION (provided by applicant): A major function of the cerebellum is motor coordination and maintenance of balance. Dysfunction of the cerebellum, either as a consequence of a hereditary disorder or acquired deficiency, results in uncoordinated movement (ataxia). There is presently no cure for any of the hereditary ataxias, and there are few effective therapeutic options for ataxia in general. However, during the last two decades serotonergic agonists have been shown to be therapeutically effective in reducing the symptoms of a wide variety of cerebellar ataxias. The mechanism of action of serotonergic drugs is not understood. Given the therapeutic utility of serotonin it is important to delineate its mechanism of action in the cerebellum as a first step towards improving its therapeutic use in ataxia. The goal of this proposal is to delineate the effects of serotonergic drugs on cerebellar Purkinje cells. In particular, we will test the hypothesis that serotonin regulates the trafficking of AMPA/Kainate receptors in these neurons. PUBLIC HEALTH RELEVANCE: A major function of the cerebellum is motor coordination and maintenance of balance. Dysfunction of the cerebellum, either as a consequence of a hereditary disorder or acquired deficiency, results in uncoordinated movement (ataxia). There is presently no cure for any of the hereditary ataxias, and there are few effective therapeutic options for ataxia in general. However, during the last two decades serotonergic agonists have been shown to be therapeutically effective in reducing the symptoms of a wide variety of cerebellar ataxias. The mechanism of action of serotonergic drugs is not understood. Given the therapeutic utility of serotonin it is important to delineate its mechanism of action in the cerebellum as a first step towards improving its therapeutic use in ataxia. The goal of this proposal is to delineate the effects of serotonergic drugs on cerebellar Purkinje cells.