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. This project elucidates the pathophysiologic mechanisms of abnormal behaviors in Parkinson's disease (PD) in view of developing new therapeutic tools. Our goal has been to characterize basal ganglia functional alterations as shown by changes of regional neuronal activity. During the reporting period, we analyzed most electrophysiology data of single cell recording from the external segment of the globus pallidus (GPe). Firing rates were profoundly decreased in the 'off' state (rates averaged 32 Hz), and the substantial decrease of GPe activity indicates a marked inhibitory input from the indirect striatal output pathway as a result of profound dopamine denervation. Dopamine stimulation increased firing rates in the majority of neurons in all three groups as classified according to their firing pattern (pausers, non-pausers, and bursters). We found that dyskinesias (involuntary movements) are associated with inversion of the rate changes that had occurred at the onset of the dopamine response. Such bidirectional response was found in 50% of total neurons. The remaining half of neurons continued to increase or decrease the firing frequency during dyskinesias exhibiting unidirectional responses. Thus, dyskinesias are expressed with marked differences of neuronal activity across GPe units; unidirectional changes lead to much higher frequencies in most units while bidirectional changes result in a return to the baseline frequency. These findings contribute critical information to the pathophysiology of abnormal motor behaviors in PD; for instance our results contradict the notion that an imbalance of striatal activity may reduce the participation of the direct or indirect striatal output pathways in dopamine responses. A better understanding of the mechanisms underlying abnormal behaviors may help develop new and more specific therapies.