In human patients with parkinsonism, the motor symptoms (bradykinesia, resting tremor, rigidity) can be relieved by focal lesions of the internal segment of the globus pallidus. Similar results have been obtained in primate models of parkinsonism. In parkinsonism patients and in primate models of parkinsonism, the electrical activity of globus pallidus neurons is abnormal. Unlike neurons from normal animals, an unidentified subpopulation of GP neurons in these animals exhibit synchronous, rhythmic discharge. It has been hypothesized that this abnormal activity is responsible for the motor symptoms in PD and served as the rationale for surgical intervention. This abnormal activity can be attributed to an interaction between the intrinsic properties of GP neurons and altered synaptic input following dopamine depletion. It is our working hypothesis that this altered synaptic input arises either from striatum or from the subthalamic nucleus (STN). To test this hypothesis, a combination of whole-cell voltage clamp, flurometric and single cell RT-PCR techniques will be used to address three specific aims.
Specific Aim 1 is to characterize the cellular/molecular determinants controlling the emergence of rhythmic activity in identified GP/EP neurons following dopamine depletion. Our working hypothesis is that elevated enkephalin released and diminished substance P/dynorphin and dopamine release subsequent to dopamine depletion promote burst firing and rhythmicity in GP neurons that do not express parvalbumin.
Specific Aim 2 is to characterize the cellular/molecular determinants controlling the emergence of neuronal synchrony in identified GP/EP neurons following dopamine depletion. It is our working hypothesis that disruption of pre- and/or post-synaptic modulation of recurrent collateral GABAergic signaling in the GP leads to the emergence of synchrony.
Specific Aim 3 is to characterize the cellular/molecular determinants controlling the expression of rhythmic activity in identified STN neurons following dopamine depletion. Our working hypothesis is that dopamine suppresses rhythmic activity in STN neurons by modulating hyperpolarization activated conductances, voltage- dependent Ca/2+ conductances and the responses to GABAergic input arising from the GP. The successful attainment of these specific aims should provide much needed information about the properties of normal and dopamine-depleted GP/EP/STN neurons. With this information in hand, we should possess not only a better understanding of this critically important, yet under- studied, group of basal ganglia neurons, but we should also be in a position to devise more effective and less invasive treatments for Parkinson's disease than irreversible lesioning.
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