MOLECULAR PHYSIOLOGY OF NMDA RECEPTORS

We are currently investigating the hypothesis that NMDA receptors are frequency discriminators which serve to translate information encoded within the frequency of the arriving stimulus into distinct intracellular calcium concentrations which trigger appropriate intracellular plastic events (LTP/LTD). Further, we aim to characterize how modulators acting specifically on the receptor's frequency sensitivity affect the frequency function for plasticity at hippocampal synapses.

Glutamate is the golden coin of information transfer in the central nervous system. More than 80% of neurons and 90% of synapses are glutamatergic. Most of these synapses use a combination of receptors to "sense" glutamate: the AMPA and kainate receptors and the NMDA receptors. Never mind the cryptic names; these are proteins which bind glutamate with characteristic kinetics and respond by opening an intrinsic pore which allows Na+, K+ and Ca2+ to flow freely across the cell membrane. These cationic currents although tiny (only a few picoamperes) , mediate fundamental neuronal processes such as synaptic transmission and plasticity. These processes are inextricably involved in higher brain functions such as learning, memory and behavior. Glutamate receptor dysfunctions are to blame for pernicious neuropathologies associated with stroke, chronic pain, addiction, epilepsy, schizophrenia and neurodegenerative diseases (Alzheimer's, Huntington, Parkinson, ALS). A better understanding of how glutamate receptors become active, how they are modulated and how they carry on physiologic and pathologic functions will help address rationally these devastating conditions.

You may know that in response to a squirt of neurotransmitter, ligand-gated ion channels (or at least, the poster protein for these, the acetylcholine receptor) open very fast (50,000 times per every second), close and re-open a few times before the ligand dissociates and the response is thus terminated. The NMDA receptors are quite different! First, these channels open much slower (about 200 times per second) and under some circumstances they may remain active for a relatively long time (tens or hundreds of milliseconds), before glutamate dissociates to terminate the response. To understand how NMDA receptors work and thus to get a more detailed picture of the events that underlie a synaptic response (ligand binding, channel opening and closing, desensitization) we develop and test state models. An accurate state model describing the kinetic behavior of NMDA receptor channels is a helpful instrument in exploring how structure and function correlate in the NMDA receptor and in predicting receptor behaviors that are difficult to measure directly, such as channel responses at a synapse. We are currently using single-channel recordings, recombinant DNA technology and kinetic modeling to reveal the pathway of conformational change that underlies channel activation (ligand binding, gating, desensitization) and to characterize these intermediary steps and their modulation. Further we aim to understand how physiologic and pharmacologic agents modify specific activation steps and how this modulation impacts on synaptic transmission and plasticity (LTP/LTD) at several well characterized brain synapses.