REGULATION OF MOTOR FUNCTION IN PARKINSON'S DISEASE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Motor disturbances of Parkinson?s disease are caused by a series of functional alterations in basal ganglia that derive from dopamine denervation. The mechanisms underlying those functional alterations are not completely understood. Moreover, long-term levodopa therapy is usually associated with disabling motor complications of unclear pathophysiology. The objective of this project is to elucidate the pathophysiologic mechanisms of abnormal behaviors in Parkinson?s disease in view of developing new therapeutic tools. Thus, this study aims: to localize functional alterations in specific basal ganglia circuits; to determine the glutamate regulation associated with an altered neuronal function; to explore new therapeutic approaches by interacting with the glutamatergic neurotransmission in a region-specific manner. This project has made great progress during the last period, and we are completing a big part of specific aim 1. The neuronal activity of striatum has been studied in various motor conditions. We have generated abundant data to fully characterize patterns of activity that specifically correlate to motor states in parkinsonism. Recordings in other regions have started, i.e. globus pallidus, both segments. We are also working on the second specific aim by initiating autoradiography studies. Firing rates change with the reversal of parkinsonism following two directions, increase and decrease, and this is congruent with the dual action of levodopa on striatal neurons. The appearance of dyskinesias is associated with inversion in the direction of rate changes. This pattern of activity indicates that dyskinesias are produced by different mechanisms than those operating the reversal of parkinsonism. These changes are observed in striatal neurons with bursty and non-bursty activity. These cells also change patterns of activity in relation to motor states. The latest analyses of striatal activity data indicate that bursts are linked to akinesia and other features of parkinsonism, while other patterns such as pausing and irregularity correlate with dyskinesias.