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. The objective of this project is to elucidate the pathophysiologic mechanisms of abnormal behaviors in Parkinson's disease with the goal of developing new therapeutic tools. Thus, this study aims: 1-to characterize basal ganglia functional alterations, 2-to determine the glutamatergic regulation associated with an altered neuronal function, and 3-to explore new therapeutic approaches by interacting with the glutamatergic neurotransmission. This project has made great progress during the last period. Our previous findings suggested that dyskinesias are produced by mechanisms that overturn dopamine action on striatal neurons. However, the specific relationship of those rate changes to the occurrence of dyskinesias remained uncertain. This year, we recorded the activity of striatal neurons in experiments of lower doses of levodopa. Firing rates of striatal neurons did not show inversion of changes during the 'on' state when dyskinesias were not present. These results proved our novel findings of inversion of dopamine-induced rate changes in striatal neurons that is mechanistically associated with dyskinesias. Regarding the pattern of neuronal activity, we found that reversal of parkinsonian disability was characterized by a reduction of bursting and changes in burst conformation. Most 'bursty' neurons also increased their frequency during the transition to reversal of parkinsonism implying that dopamine mediates excitatory mechanisms in these neurons, thereby involving the direct output pathway. From results of pattern analysis so far, we can conclude that parkinsonian motor symptoms are associated with burst discharges in a subpopulation of striatal neurons. Drug tests performed this year indicate that ion channel blockers appear to be highly effective for initial local injections.