Ion channel mechanisms of striatal dopaminergic motor stimulation

纹状体中多巴胺的缺失会迅速导致运动障碍，这是帕金森病的一个关键病理。L -

Loss of dopamine in the striatum quickly leads to akinesia and is a key pathology of Parkinson's disease. L- dopa, via dopamine, strongly stimulates motor activity in Parkinson's disease patients and dopamine- depleted animals. However, the ion channel and neurophysiological mechanisms underlying dopamine's profound motor function remain unknown; this knowledge gap is an obstacle to improving the treatment of this disease. Using suitable mouse models with color-labeled striatonigral neurons and striatopallidal neurons and consistent dopamine denervation, and combining patch clamp recording in a well controlled brain slice preparation and tetrode spike recording in freely moving mice, this project will test our hypothesis that dopamine D1 receptor activation upregulates the subthreshold-activating and persistent sodium current in striatonigral neurons and thus, increases the motor-promoting spike output from these neurons, contributing to dopamine's motor stimulation; these effects are enhanced when the D1 receptors are supersensitive after dopamine denervation such as in Parkinson's disease. Simultaneously, dopamine D2 receptor activation downregulates the persistent sodium current in striatopallidal neurons and hence decreases the motor- inhibiting spike output from these neurons, further contributing to dopamine's motor stimulation; these effects are also enhanced when the D2 receptors are supersensitive following dopamine denervation. Preliminary results support our hypothesis. In summary, this project will use integrative approaches to define fundamental ion channel and neurophysiological mechanisms by which dopamine D1 receptor activation excites striatonigral neurons and dopamine D2 receptor activation inhibits striatopallidal neurons. Results of this research will provide critical insights into the long-standing question of how dopamine stimulates motor activity and will also lay a scientific foundation for improving the treatment for the motor symptoms of Parkinson's disease.