The basal ganglia and thalamus are interconnected through a series of loops that process and convey basal ganglia outflow to either frontal cortical regions via the ventral motor nuclei or back to the striatum via the caudal intralaminar group, namely the centre median (CM) and parafascicular (Pf) nuclei. Although the existence of a thalamostriatal system has long been established, the role of these projections in the functional circuitry of the basal ganglia remains enigmatic. For the first four years of this grant, we focused our interest on the sources and chemical nature of basal ganglia and brainstem synaptic inputs that control the activity of thalamostriatal neurons. Both the internal globus pallidus (GPi) and the substantia nigra pays reticulata (SNr) provide GABAergic afferents to specific regions of CM/Pf. In addition, the pedunculopontine tegmental nucleus (PPN) is the source of highly heterogeneous chemical inputs to CM/Pf, some of them co-localize GABA and acetylcholine. In addition, neurons in CM/Pf, as in most thalamic nuclei, are endowed with intrinsic GABAergic influences from the reticular nucleus and local interneurons. Electrophysiological data show that GABA plays a crucial role in regulating thalamic activity. However, the exact mechanisms by which GABA mediates its effects on thalamic neurons are complex and still matter of speculation. In order to further characterize this issue, we propose to use state-of- the-art immunocytochemical procedures at the electron microscopic level to elucidate the subsynaptic and subcellular localization of GABA-A and GABA-B receptors in the basal ganglia-receiving territories of the ventral motor thalamic nuclei and CM/PF in monkeys. Abnormal increased GABAergic outflow from the basal ganglia to the thalamus is a cardinal feature of Parkinson's disease pathophysiology. Such increased activity likely results in downregulation of postsynaptic GABA receptors in basal ganglia receiving thalamic nuclei. In order to elucidate this issue, another goal of this project is to compare the pattern of subsynaptic localization of GABA-A and GABA-B receptors in CM/Pf and ventral motor nuclei of normal monkeys and animal models of Parkinson's disease. This series of studies should provide a comprehensive analysis of GABA receptors localization at specific synaptic sites in basal ganglia-receiving thalamic nuclei in primates. Such information is critical for the interpretation of functional studies and a better understanding of the pathophysiological changes generated at pallidothalamic and nigrothalamic synapses in Parkinson's disease.
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