Grant: Doctoral Research Award: Canada Graduate Scholarships

Huntington disease (HD) is an inherited neurological disorder characterized by involuntary movement, loss of motor control, and cognitive deficits. HD involves disrupted signaling in the striatum, a brain region important for motor learning and coordination. Glutamate (GLU)-releasing terminals from the cortex synapse onto striatal neurons, forming a gateway for regulating coordinated movement. Dopamine (DA), acetylcholine (ACh) and endocannabinoids (eCB) modulate activity at this synapse, and the corticostriatal impairments that occur early on in HD are likely attributed to impaired signaling of these neuromodulators. We have recently found that D2 DA receptors in HD mouse brain slices are more sensitive for reducing cortically-evoked GLU release in the striatum when compared to healthy mice. We have also found that chronic treatment with a drug that enhances eCB signaling can rescue motor learning in HD mice. This study aims to explore the interplay between DA, eCB and ACh signaling on GLU transmission and motor learning in a transgenic mouse model of HD. Aim 1: To investigate the mechanism underlying enhanced suppression of GLU release mediated by increased D2 receptor activity in HD mice. Aim 2: To monitor GLU and eCB signaling in mice during motor learning and test different drug interventions. By imaging neurotransmitters with fluorescent probes, this study will be the first to our knowledge to directly image eCB and ACh signaling in live HD striatal slices and in freely-moving HD mice. This project will provide significant contributions to the health sciences field by elucidating the role of DA, eCBs and ACh in modulating GLU transmission in HD, advancing current knowledge on the neuromodulatory mechanisms that give rise to motor symptoms in HD. Results obtained will have significant translational potential, as the specific drugs used in this study directly affect signaling systems that are impaired in human HD patients.