Inhibitory Control of Medium Spiny Neurons

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DESCRIPTION (provided by applicant): This project aims to compare phasic and tonic GABAA receptor-mediated currents and the receptor subtypes that mediate them in striatopallidal versus striatonigral medium spiny neurons (MSNs). MSNs are GABAergic neurons which make up 95% of the cells in the striatum. They primarily receive their inhibitory input from local GABAergic interneurons and axon collaterals of neighboring MSNs. The striatonigral MSNs project to the substantia nigra, express dopamine Dl receptors and are thought to facilitate movement whereas the striatopallidal MSNs project to the globus pallidus, express dopamine D2 receptors and are thought to inhibit movement. Parkinson's disease (PD) is a neurological disorder that results from a loss of DA innervation to the striatum and is characterized by impaired initiation of movement, resting tremor, postural instability and rigidity. Although the underlying mechanism remains unknown, an abundance of studies have suggested that the motor impairments seen in PD arise from an overactive output of the D2 positive MSNs that follows loss of dopaminergic innervation. It is unclear why the increased output is selective for the striatopallidal MSNs, however, identifying ways to selectively reduce the activity of the striatopallidal MSNs holds significant therapeutic potential for the treatment of the motor symptoms in PD. For this study, we will utilize corticostriatal slices made from two strains of mice which selectively express green fluorescent protein in either Dl expressing or D2 expressing cells to identify unique properties of receptors that mediate inhibitory currents in these cells. The properties of the GABAA receptors which mediate both the phasic and the tonic inhibition as well as the function of these currents on cell excitability and NMDA receptor activation will be assessed using single cell electrophysiological recordings in conjunction with immunofluoresence with confocal microscopy. In addition to potentially identifying new therapeutic targets in the GABAA receptor family for treatment of PD, the results of this study will significantly improve the understanding of striatal circuitry. This understanding is fundamental for future progress in treatment of PD as well as other striatal disorders like Huntington's disease, Tourette's, tardive dyskinesia and drug addiction.