In the past few years, evidence from both experimental and clinical studies suggests a key role for the subthalamic nucleus in the pathogenesis of Parkinson's disease. As the principal excitatory pathway interconnecting basal ganglia nuclei, it is one of the most likely suspects as the origin of the synchronous rhythmic firing patterns in the globus pallidus that are associated with the motor symptoms of that disease. In slices of the subthalamic nucleus, the neurons spontaneously fire rhythmically at a rate approximating that seen in dopamine-denervated animals and in Parkinsonism in humans. The proposed experiments will determine the ionic mechanisms responsible for the rhythmic firing of subthalamic neurons seen in slices, and determine the degree to which rhythmic activity may become synchronized by recurrent excitatory interactions between subthalamic neurons. The experiments will employ infrared-visualized whole cell recording, imaging of calcium entry during spontaneous and evoke rhythmic firing, and intracellular staining of recurrent axonal connections. A possible role of extrinsic excitatory inputs in desynchronizing the cells of the nucleus, and in disrupting their rhythmic activity will be explored by micro-stimulation and cortico- subthalamic fibers in slices preserving a portion of that pathway. A knowledge of the mechanism underlying rhythmic and possibly synchronous activity in vitro may offer new pharmacological approaches to treatment of the motor symptoms of Parkinson's disease, and provide a more mechanistic explanation of stereotaxic surgical treatments currently in use.
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