Kainate Receptors in the Striatum: Implications for Excitotoxicity in Huntington's Disease

Huntingtons disease HD is a neurodegenerative condition characterized by a loss of projection neurons in the striatum. Although various hypotheses have been proposed to explain the mechanisms that underlie the striatal neuronal death, excitotoxicity still deserves major interest. Recent findings indicate that changes in the genotype of the kainate receptor subunit, GluR6, are associated with variation in the age of onset of RD, which implicates the kainate receptors in the pathogenesis of RD. The rationale of this project is that pre-synaptic kainate receptors control the release of glutamate from cortical or thalamic terminals, and that an abnormal regulation of these receptors is involved in the death of striatal neurons in HD. We, therefore, propose to use state-of-the-art electron microscope techniques to test a series of hypotheses that will help to elucidate the localization and understand better the role of kainate receptors in the primate striatum. The results of these studies will provide a strong basis for studying the potential mechanisms by which these receptors participate in the death of striatofugal neurons in RD. Moreover, they will help the development of novel therapeutic strategies aimed at targeting pre- synaptic kainate receptors in RD and other basal ganglia disorders.