We are interested in mechanisms of excitotoxic neuronal injury and in developing methods for neuroprotective intervention. Purkinje cells are integrative neurons of the cerebellar cortex and are highly susceptible to a variety of insults, both experimental and clinical. The explanation for the heightened susceptibility of these neurons remains uncertain. Together with Mark Molliver, we have developed an in vivo animal model of Purkinje cell degeneration in which neurotoxic alkaloids, including ibogaine and harmaline, cause prolonged activation of inferior olive neurons that results in trans-synaptic, excitotoxic degeneration of Purkinje cells. Climbing fiber axons from inferior olive neurons are glutamatergic and innervate Purkinje cells in a uniquely dense fashion, a factor which may underlie the susceptibility of Purkinje cells to injury. Through pharmacologic modulation of drug-induced Purkinje cell degeneration we are focusing on the contribution of specific glutamate receptor subtypes and on signal transduction mechanisms that lead to Purkinje cell death. Analysis of this injury cascade should reveal therapeutic targets that can be manipulated pharmacologically to prevent neuronal damage in human cerebellar disorders.

   An associated interest is in relating mechanisms of neuronal injury to clinical neurologic disease in human patients. In collaboration with colleagues in Psychiatry, Neuropathology and Neuroscience we are studying patients with degenerative disorders such as spinocerebellar ataxia type 12 (SCA12) and Huntington’s Disease-Like 2 (HDL2). Our goals include relating genetic abnormalities, such as expanded trinucleotide repeats, to cellular mechanisms that result in neuronal degeneration.