The dysfunction and therapeutic potential of the endocannabinoid system in Huntington's disease

Abstract

Huntington's Disease is an autosomal dominant progressive neurodegenerative disease, which features profound disturbance of the basal ganglia, and in particular medium spiny neurons of the caudate/putamen. Of the many molecular changes that accompany this disease, impaired endocannabinoid signaling is among the earliest and most well-described. The purpose of this thesis is to describe the contribution of impaired endocannabinoid signaling to the progressive Huntington's phenotype, and to test the potential for leveraging the protective nature of endocannabinoid signaling to control some features of the disease, including seizures. We report that genetic rescue of endocannabinoid signaling in a mouse model of Huntington's disease prevents synaptic loss in the striatum, but does not block the development of a motor phenotype, suggesting an unexpected uncoupling of these pathogenic mechanisms. Additionally, we describe a pharmacologic approach to augment endocannabinoid signaling in order to control both chemically-induced convulsions and spontaneous seizures in a mouse model of Huntington's disease, and conclude that this approach might represent a novel antiepileptic strategy.