Heterogeneity of synaptic NMDA Receptors

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DESCRIPTION (provided by applicant): A delicate balance of information to and from the striatum controls the execution of learned motor behaviors as well as the suppression of unwanted movements. The striatum receives converging glutamatergic innervation from the cortex and thalamus and dopaminergic innervation from the substantia nigra and these two neurotransmitters modulate the function of one another in order to maintain the proper balance of information outflow for smooth control of motor output. The main neuronal type in the striatum, the medium spiny neuron (MSN) is a recipient of these inputs express receptors for both glutamate and dopamine neurotransmitters. This project aims to compare N-methyl-D-aspartic acid receptors (NMDARs) receptor-mediated currents and the receptor subtypes that mediate them in striatopallidal versus striatonigral MSNs. We will utilize corticostriatal slices made from two strains of mice which selectively express green fluorescent protein in D1 or D2 dopamine receptor expressing cells to identify unique properties of NMDA receptors in these cells. Single cell electrophysiology in corticostriatal slices will be used to test the hypothesis that that a portion of striatal NMDA receptor have unique properties and are unequally distributed between the two major subtypes of striatal projection neurons. Based on preliminary data showing that MSN express a subtype of NMDA channel that once activated can open and close repetitively for a long time, the first specific aim will compare the function and pharmacology of synaptic and extrasynaptic NMDA receptors between D1 and D2 MSNs and will test the hypothesis of the involvement of the triheteromeric NR1/NR2B /NR2D receptors. The second aims will follow exciting leads that dopamine depletion and L-Dopa treatments regulate the distribution of NMDA receptor subtypes via synaptic regulatory proteins and will study the functional consequence of the activation of distinct dopamine receptors on NMDA receptor subtypes. PUBLIC HEALTH RELEVANCE: The results of our studies will fill a gap in the understanding of the role of NMDA subtype of glutamate receptor in striatal function and control of movements. Characterizing NMDA receptors in medium spiny neurons expressing distinct dopamine receptor subtypes will allow a unique opportunity to answer a fundamental question: How dopamine receptors regulate striatal function via glutamate receptors? This answer to this question will have great potential to understand the etiophatology of striatal neurodegeneration and will identify new therapeutic targets in the NMDA receptor family for treatment of movement disorders.