Therapeutic potential of the endocannabinoid system in a novel mouse model of Huntington’s Disease

Abstract

Huntington’s Disease is a fatal, inherited neurodegenerative disease characterized by profound disturbances of the basal ganglia and gradual deterioration of motor and cognitive functions with development of psychiatric deficits. Early impairment of the endogenous cannabinoid signaling system is thought to be one of many hallmarks of this neurodegenerative disease and a possible molecular event that drives disease pathogenesis. Reduction of this system suggests absence of its many neuroprotective qualities and that this may contribute to the neuropathology in Huntington’s Disease. The purpose of this thesis is to characterize novel lines of the HdhQ mouse model that accurately recapitulate Huntington’s Disease and to use that model to explore the therapeutic potential of the endogenous cannabinoid signaling system in delaying or preventing disease development. In this thesis, I report that the HdhQ350/+ model, the HdhQ line expressing 350 polyglutamines, exhibits both sex-dependent behavioral impairments and neuropathology despite males and females expressing equal mutant huntingtin protein levels, suggesting a sex-dependent effect of expanded polyglutamines in mouse models. Additionally, I report that the HdhQ200/200 mouse, the line homozygous for 200 polyglutamines, more accurately replicates Huntington’s Disease, both behaviorally and pathologically. Short-term pharmacological enhancement of endogenous cannabinoids in this mouse model through ABHD6 inhibition shows potential in rescuing select behavioral impairments. Together, this doctoral thesis puts forth efforts to understand the impact of polyglutamine expansions in mouse models and to uncover a novel therapeutic in the treatment of Huntington’s Disease by exploring the promising domain of the endocannabinoid signaling system.