GABAergic Signaling in the External Globus Pallidus

Parkinson’s disease (PD) is the second most common neurodegenerative disease associated with aging. The disease is characterized by motor symptoms attributed to the loss of mesencephalic dopaminergic neurons and their innervation to the basal ganglia macrocircuit. In patients and animal models of PD, this macrocircuit exhibits aberrant activity patterns including synchronous, rhythmic bursting of neurons in the external globus pallidus (GPe). However, the factors that shape these synchronous and temporally­structured events in PD remain unknown. It is our overarching hypothesis that GABAergic inputs shape the activity level, pattern, and synchrony of both parvalbumin and Npas1 neurons within the GPe. Using cell­ and circuit­specific tools, we will investigate the connectivity of striatal inputs and local collateral inputs to parvalbumin and Npas1 neurons within the GPe and how this connectivity becomes altered in the chronic 6­OHDA lesion model of PD. Furthermore, we will determine how parvalbumin and Npas1 neurons and their striatal inputs are involved in motor function and dysfunction. The proposed experiments capitalize on a combination of cutting­edge approaches that will overcome obstacles that had impeded progress until now. These approaches include viral gene delivery, Cre­lox recombination, optogenetics, chemogenetics, electrophysiology, and fiber photometry. Additionally, anatomical, analytical, and computational approaches will be used to help interpret research findings. The successful achievement of these aims will significantly advance our understanding of the mechanisms underlying PD and, in doing so, promote the development of new therapies for PD patients.