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Vikram Shakkottai

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Primary Appointment: Neurology Department
Primary PIBS Dept.: Neuroscience
Other PIBS Depts.: Molecular and Integrative Physiology
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  The ataxias are a heterogeneous group of disorders with degenerative changes primarily in the cerebellum and brain stem. The most common dominantly inherited degenerative ataxias result from mutant proteins that are expressed widely in neuronal and non-neuronal tissues, yet preferentially affect neurons of the cerebellum and brainstem. The basis for the preferential vulnerability of specific neuronal populations remains unclear. Intriguingly, many of the most affected neurons in the degenerative ataxias exhibit autonomous pacemaker firing (spontaneous rhythmic firing even in the absence of synaptic input). My laboratory is interested in determining if the unique physiology of these pacemaker neurons predisposes them to selective vulnerability in degenerative ataxias.

Defining early physiologic changes in the ataxias is important because such changes represent outstanding therapeutic targets for symptomatic and preventive treatment of neurodegenerative disorders. My laboratory seeks 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, immunohistochemical techniques and in vivo drug delivery 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 also perform unit recordings in awake mice.