The regulation of globus pallidus gene expression by dopamine and the subthalamic nucleus.

摘要

Parkinson's Disease (PD) is a neurodegenerative disorder affecting the dopaminergic neurons of the substantia nigra pars compacta (SNc). SNc neurons extensively innervate a group of subcortical nuclei known as the basal ganglia. Most research to date has focused on the result of dopamine (DA) loss in the striatum, the main input structure of the basal ganglia. However, extrastriatal structures also receive substantial DA innervation, though the effects of DA and of DA loss in these areas are less well understood. The experiments presented in this dissertation were designed to explore the effects of reduced DA tone in the globus pallidus (GP), the second largest basal ganglia nucleus and a critical component of the “indirect pathway”. DA can act directly in the GP via D2 receptors and these effects of DA may explain some seemingly paradoxical results in the literature concerning alterations in GP activity in animal models of PD.; The first study demonstrates that intrapallidal administration of the D2 antagonist, sulpiride, induced immediate early gene (IEG) expression in the GP. This EEG induction occurred predominantly in pallidal neurons which lack the calcium-binding protein, parvalbumin (PV) and are more likely to project to the striatum than to the subthalamic nucleus (STN) or basal ganglia output nuclei. The second study examined the population specificity of long-term changes in pallidal gene expression. Following 6-OHDA lesion or repeated D2 antagonist administration, levels of GAD₆₇ mRNA increase in both PV+ and PV− GP neurons, but this increase is significantly more pronounced in PV− GP neurons. The last study examined the regulation of GP late-gene expression by dopamine and the STN. STN lesions abolished the 6-OHDA or D2 antagonist-induced increase in GAD₆₇ mRNA in PV+, but not PV− pallidal neurons. These finding suggest that STN lesions preferentially regulate GAD₆₇ mRNA expression in PV+ GP neurons, whereas 6-OHDA lesions or repeated D2 antagonist administration preferentially regulate GAD ₆₇ mRNA expression in PV− GP neurons.; The studies presented in this dissertation support a growing body of research suggesting that dopaminergic input to the GP, as well as dopamine-glutamate interactions in the GP, play critical roles in basal ganglia dysfunction.