HETEROGENEITY OF SYNAPTIC NMDA RECEPTORS

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I am currently an Associate Professor in the Department of Physiology at Georgetown University. My long term research goal is to understand the role of the large heterogeneity of molecular forms of amino acid receptors as determinant of the strength and of long-term modifications of synapses in the central nervous system, relevant to most brain function and to the pathogenesis of neuropsychiatric disorders. I am investigating the hypotheses that NMDA receptor (NMDAR) subunits composing postsynaptic receptor-channel complexes play a major role as determinants of synaptic strength. This work has been the basis for my research funding support for the last 8 years as a member of a Program Project on excitatory amino acid receptors of which I was principal investigator of one of the project. For the last five years my research endeavor was also supported by a RCDA award from the NINDS based on that project. I recently resubmitted my component of the program project as an independent R01 for competitive renewal that has just been reviewed and received a percentile ranking (9.6 percent) within the funding range. Although this support was essential to my development I still feel that by minimizing my teaching and administrative responsibilities, the new award will allow for personal growth at several levels. The additional time will permit me to gain strengths in understanding how the heterogeneity of molecular forms of NMDA receptor at excitatory synapse and their posttranslational modifications underlie the effectiveness of the NMDA component of EAA mediated synaptic transmission and in turn synaptic plasticity. The functional diversity of synaptic and extrasynaptic NMDAR in distinct neuronal populations in brain slices and primary culture will be investigated with electro- physiological, anatomical and pharmacological techniques. Preliminary results suggest roles for subunit heterogeneity and posttranslational modifications in producing distinct kinetics of synaptic NMDA currents in cortical neurons. Experimental strategies will be used to regulate function and expression of distinct NMDAR subtypes neurons resulting in the understanding of how neuronal activity, protein kinases and neurotrophins controls the expression of NMDA receptor subtypes. Data obtained from these specific aims will permit the understanding of the molecular determinant responsible for synaptic plasticity in CNS possibly relevant o for the understanding of neuropsychiatric disorders.