| Popis: |
Huntington disease (HD) is a progressive neurodegenerative disorder with no disease-modifying treatments. Patients experience motor, cognitive, and psychiatric disturbances, and the dorsal striatum is the main target of neurodegeneration. Mouse models of HD show altered striatal synaptic signaling in vitro, including changes to cortico-striatal glutamate signaling. Previous studies demonstrate altered glutamate receptor distribution and signaling at cortico-striatal synapses in HD mice, and some studies suggest that glutamate release may be altered, but the presynaptic mechanisms underlying aberrant glutamate release in HD are unknown. Additionally, although changes to striatal signaling have been studied extensively in vitro, it is unclear how these changes correlate with behavioural impairments in vivo. Here, we utilize optogenetic sensors to explore cortico-striatal signaling in HD mice. In acute brain slice, we used iGluSnFR, a modified green fluorescent protein reporter for real-time imaging of glutamate dynamics, to study the presynaptic modulation of glutamate release. We validated iGluSnFR as a valuable tool to accurately measure short- and long-term changes in glutamate release caused by changes to extracellular calcium levels, modulation by presynaptic receptors, and plasticity-inducing stimulation protocols. We confirmed a deficit in HFS-LTD and found changes to D2-receptor-mediated inhibition of glutamate release in YAC128 HD mice. In vivo, we used GCaMP7f, a calcium-sensing fluorescent reporter, to image striatal activity during motor learning on the accelerating rotarod and open field exploration. Mice showed increased neuronal activity on the rotarod, which diminished by late stages of learning. 2–3-month-old YAC128 mice did not show a deficit in latency to fall, but did display significant deficits in paw kinematics, including increased frequency of paw slips. These mice also exhibited aberrant striatal activity during rotarod performance, including a weaker correlation between striatal activity and behaviour. 6–7-month-old YAC128 mice displayed severe rotarod deficits, and elevated striatal activity while on the rotarod. In the open field, YAC128 mice showed increased neuronal activity at rest. Overall, this thesis presents new insights into the mechanisms underlying cortico-striatal glutamate transmission, and alterations to striatal activity associated with behavioural impairments, in mouse models of HD. |
