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Alcohol is a known neurotoxin. Acute alcohol toxicity includes a loss of motor coordination, with an impairment of gait and speech. Now imagine similar symptoms that are persistent and progressive. This describes a group of clinical disorders known as the ataxias. The ataxias are a heterogeneous group of disorders with degenerative changes primarily in the cerebellum and brain stem.
We are interested in alterations in cerebellar physiology in the cerebellar ataxias. Defining early physiologic changes in the ataxias is important because such changes represent therapeutic targets for symptomatic and preventive treatment of neurodegenerative disorders. We seek to tie changes in neuronal firing properties to defects in specific ion channel proteins. Merely demonstrating that neurons have changes in firing properties would have a limited impact on therapy; after all, in a degenerative disorder one would expect that global cellular dysfunction would also lead to changes in membrane properties. We seek to identify specific changes in the properties of ion channels and whether compensating for these changes using ion channel modulators can restore normal physiology and improve motor function. Currently, no symptomatic or preventive therapies exist for degenerative ataxias. Among the questions that we seek to answer is whether ion channel channel modulators, by restoring normal physiology, represent viable therapeutic reagents in ataxic disorders.
We use a combination of single cell electrophysiology, biochemistry, and immunohistochemical techniques to investigate the role of ion channels in normal neuronal function and in disease. We use patch clamp techniques in brain slices, dissociated neurons and in cell lines stably expressing ion channel subunits. We use this in combination with histologic techniques and in vivo drug delivery to identify promising treatment candidates.
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