Grant: Doctoral: Vanier Canada Graduate Scholarships

Huntington disease (HD) is a devastating neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. Mutation of HTT causes selective and progressive degeneration of the striatum, leading to chorea. In both humans and mouse models of HD, synaptic function is disturbed long before observable symptoms occur. It is believed that these initial changes promote later striatal dysfunction and ultimately neuronal death. Thus, modulation of key pathways at presymptomatic stages represents an attractive approach to thwart disease progression, particularly because of the genetic predictability of HD. One of the earliest features to be observed in HD models is overactivation of striatal GluN2B-type NMDA receptors which bind to the excitatory neurotransmitter glutamate. In HD, these receptors are incorrectly localized outside of synapses to extrasynaptic sites, where they are coupled to intracellular signaling pathways which promote cell death. The aim of this research proposal is to chronically inhibit this extrasynaptic signaling pathway in the YAC128 HD mouse model in order to reverse molecular and behavioural pathology. I will do this using two complementary strategies: selective blockade of GluN2B receptors and inhibition of the downstream cell death-promoter p38 MAPK. Currently, no disease-modifying therapies exist for HD. My proposed research is constructed upon many years of evidence to suggest that NMDA toxicity is a key contributor to HD, and therefore has excellent potential to ultimately translate into clinical benefit. Additionally, a variety of neurodegenerative diseases and acute conditions such as ischemia are known to involve glutamate toxicity. The definitive genetic nature of HD makes it a unique model which may be used to provide insight into the pathology of many neurological conditions.