GABA channels and dopamine in striatum

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DESCRIPTION (provided by applicant): The striatum controls the execution of learned motor behaviors as well as the suppression of unwanted movements. The main neuronal type in the striatum, the medium spiny neuron (MSN), receives converging glutamatergic innervation from the cortex and thalamus and dopaminergic innervation from the substantia nigra. In addition a small population of GABAergic interneurons controls the excitability of a vast population of MSNs to maintain the proper balance of information outflow for smooth control of motor output. This control is exerted via both phasic and tonic GABAa receptor activation. This project aims to compare GABA receptor-mediated currents and the receptor subtypes amongst MSNs originating the striatopallidal and the striatonigral pathways. We will utilize corticostriatal slices made from strains of mice which selectively express green or red fluorescent protein in D1 or D2 dopamine receptor expressing cells to identify unique properties of GABAa receptors in these cells. Single cell electrophysiology in corticostriatal slices will be used to test the hypothesis that that a portion of striatal GABAa receptors have unique properties and are unequally distributed between the two major subtypes of striatal projection neurons. Based on preliminary data showing that striatopallidal MSN express a tonic conductance mediated by a subtype of GABAa channel, the first specific aim will strive to understand the role of alpha and beta subunits of GABAa receptors in producing this tonic activation in MSNs. This will be done with subunit selective drugs, mice lacking specific subunits and recombinant GABA channels relevant to striatal MSNs. The second aims will test the hypothesis that protein kinase phosphorylation regulates the functional properties of tonically active GABA channels. The last aim will investigate if the presence of the specific and distinct dopamine receptors in MSN subtypes plays a role in setting the properties and regulating the expression of GABA receptor subtypes that can be target for pharmacological therapy of disorders associated with striatal dysfunction.