GABAergic transmission is mediated through two major receptor subtypes, GABA-A and GABA-B receptors. GABA-B receptors (GABA-BRs) are composed of GABA-BR1 and GABA-BR2 subunits. During the past funding period, we have described in detail the subsynaptic localization of GABA-BR1 and GABA-BR2 in the monkey basal ganglia. We found that most pallidal GABA-BRs are extrasynaptic in location. Through the use of electrophysiological, pharmacological and neurochemical approaches, we have also studied the effects of GABA-BRs activation on the neuronal activity and neurotransmitter release in the monkey globus pallidus. These studies highlighted not only the effects of GABA-BRs, but have also shown that GABA reuptake mechanisms, utilizing the GABA transporter (GAT), regulate the activation of extrasynaptic GABA- BRs in the primate pallidum. Activation of postsynaptic GABA-BRs in the basal ganglia occurs predominately with intense GABA release, e.g., during burst firing under physiologic conditions. Knowing that synchronized burst firing of GABAergic neurons in the basal ganglia is a key ingredient of the pathophysiology of Parkinson's disease (PD), we hypothesize that GABA-BRs in structures like the external pallidal segment (GPe), which is exposed to increased GABAergic drive from the striatum in parkinsonism, may display significant changes in localization and function in PD. GPe is part of the 'indirect' pathway of the basal ganglia. This pathway originates from the striatum and traverses GPe and the subthalamic nucleus (STN) en route to the basal ganglia output structures, the internal globus pallidus (GPi) and the substantia nigra pars reticulata (SNr). Increased activity along the striatum-GPe pathway in parkinsonism results in compensatory changes in GABA-B receptor distribution. The functional impact of these changes remains to be established. In this project, we propose to use high resolution electron microscopic immunocytochemistry, combined with in vivo and in vitro electrophysiologic techniques to characterize and compare the localization, trafficking and synaptic activation of GABA-BRs and the functional interplay between GAT and GABA-BRs in the basal ganglia of normal and parkinsonian animals. Studies proposed in this application will lay the foundation for a deeper understanding of the functions of GABA-BRs in the basal ganglia, and their role in the alteration of basal ganglia function in PD. ? ? ?
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