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.

Public Health Relevance

Striatopallidal and striatonigral medium spiny neurons are the major output neurons from the mammalian striatum, control movements and become imbalanced in movement disorders. Previous reports have suggested that dopamine depletion induces changes in GABA receptors which exacerbate this imbalance of striatal output. Additionally, the systemic administration of the GABAA receptor agonist muscimol, increased locomotor activity in dopamine receptor D2 knockout mice, a model of Parkinson's disease while reducing locomotion in wild type mice. Using transgenic mice with the two major striatal output pathways labeled, we will have a unique opportunity to answer a fundamental question: What role tonic and phasic GABA conductance plays in striatal disorders? As GABAa receptor have a quite established pharmacology, the proposed study has great potential to identify novel therapeutic targets for treating disorders associated with striatal dysfunction including Parkinson's disease, Huntington's disease, tardive dyskinesia, Tourette's syndrome and drug addiction. In addition, as the pharmacology of two major classes of DA receptors has such critical role in mental illness, the results we will derive, although clearly related to basic neuroscience, will have notable applications to both neurological disorders and to mental health.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Nadler, Laurie S
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Georgetown University
Schools of Medicine
United States
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