Parkinson's disease (PD) is the second most common neurodegenerative disease in the U.S. The core motor symptoms of PD are attributable to the degeneration of the mesencephalic dopaminergic neurons and alterations in the activity of neurons in the basal ganglia. In PD patients and in primate PD models, neurons in the external segment of the globus (GPe) of the basal ganglia spike in synchronous, high frequency rhythmic bursts. This pathophysiological activity is thought to be responsible for bradykinesia, akinesia, and rigidity in PD patients. The prevailing model that has dominated the field for the last two decades assumes an elevation in striatopallidal (CPu-GPe) GABAergic inhibitory input to the GPe following dopamine depletion. However, this conjecture has not been experimentally established. In particular the cellular and molecular determinants that regulate the transmission at the CPu-GPe synapse have not been fully understood. More importantly, their adaptations in disease state remain completely unexplored. In this proposal, we hypothesize that both pre- and post-synaptic alterations of the CPu-GPe occur as a result of dopaminergic denervation within the basal ganglia circuit, contributing to the motor symptoms of the disease. By blending electrophysiological, pharmacological, transcriptomic, and immunocytochemical analyses in mouse models of PD, this project pursues three specific aims addressing the basic mechanisms underlying GABAergic input to the GPe. Using mouse models of PD, we aim to identify and ultimately reconcile specific molecular changes in the striatopallidal synapse.
Our aims are: 1) To characterize the physiological properties of the striatopallidal synapse. 2) To characterize the GABAA receptor subtypes expressed in GPe neurons. 3) To characterize the interaction between striatopallidal input and intrinsic conductances of GPe neurons.
These studies are aimed at correcting dysfunctional brain activity in late stage PD. The successful attainment of our aims could not only provide a novel therapy for late stage PD but open new avenues for pharmacological treatment.
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