The hypothesis to be examined in this project is that loss of nigrostriatal dopamine (DA) neurons in Parkinson's disease (PD) and in animal models of PD1 as well as the pharmacological and surgical treatments of PD alter the functional characteristics of glutamate, Y-amino butyric acid (GABA) and DA receptors in subthalamic nucleus (STN) neurons. The STN has become important for understanding changes in basal ganglia function in PD since it is clear that one outcome in PD is a marked change in the activity of STN neurons. The current model of why STN neuronal activity changes is based on the hypothesis that DA loss in PD leads to a release of the STN from tonic inhibition by the extemal pallidurn. Increased activity of the STN, the only excitatory projection nucleus in this systern1 then provides the major excitatory drive onto basal ganglia outputs. There is a growing consensus that this model of PD is unsatisfactory. Thus, this project is aimed at examining other alternatives. We will use in vifm electrophysiology in STN slices to examine changes in receptor function after unilateral DA depletion and after three treatment paradigms, the classic, chronic L-DOPA treatment, the recent approach of deep brain stimulation of the STN, and a novel approach of implanting GABA-producing cells into the STN. There are four aims that will test our central hypothesis.
Aim I will determine if DA depletion alters responses mediated by activation of specific glutamate receptor subtypes and GABA receptors in STN neurons.
Aim II will determine if DA depletion alters subsequent DA modulation of responses mediated by activation of specific glutamate receptor subtypes and GABA receptors in STN neurons.
Aim III will test the hypothesis that treatment with L-DOPA after DA depletion restores normal responses to the activation of glutamate, GABA/A and DA receptors in the STN.
Aim I V will test the hypothesis that implantation of cells that produce excess GABA in STN or deep brain stimulation of STN after DA depletion (two procedures that silence STN neurons) alter abnormal responses induced by activation of glutamate, GABA/A, and DA receptors in either the entopeduncular nucleus (homologue of the internal pallidal segment of primates) and/or the substantia nigra pars reticulata. The results from this project, combined with those from Projects 1 and 3, will provide a more complete understanding of the mechanisms underlying changes in STN neural activity to design new, rational pharmacotherapies for PD that can use the STh as a therapeutic target.
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