ASPET Meeting Report Glutamate 2000: Old Dog, New Tricks

Glutamate continues to surprise us. Today’s graduate students will find it hard to believe that a mere 25 to 30 years ago proponents of a neurotransmitter role of glutamate were decidedly avant-garde and that the suggestion that glutamate might play a specific role in the pathophysiology of neurological and psychiatric diseases was considered heretic at best. What a difference a few years can make: by the mid-1980s, glutamate was widely accepted to be the major excitatory neurotransmitter in the mammalian central nervous system, excitotoxicity had become a neuroscientific household term, and the pioneers of the day began to advocate the development of “glutamatergic” drugs to combat human brain diseases. These appealing concepts persuaded some of the best minds in the neurosciences to study glutamate neurotransmission in depth. In rapid succession, we learned about the existence of distinct ionotropic and metabotropic receptors and their unique and discretely localized regulatory sites and processes. Molecular biological techniques uncovered a surprisingly diverse family of glutamate transporters, identified receptor subunits, and provided mice with targeted deletion or overexpression of certain glutamatergic functions. The use of molecular tools further solidified the central importance of glutamate neurotransmission in the normal development and function of the mammalian brain and its critical role in diseases of the central nervous system. The involvement of glutamatergic neurotransmission in brain physiology and pathology, and the ever increasing number of new molecular targets for glutamatergic drug development, has provided a bonanza for pharmacological research. The recent, third ASPET-Ray Fuller Symposium was therefore a timely attempt to review current knowledge in the field and to evaluate emerging concepts with an eye toward pharmacological exploitation. The one-and-a-halfday meeting, named in memory of one of the major figures of contemporary psychopharmacology, brought together experts from the preclinical and clinical realm who presented complementary, and often synergistic, data to an audience from academia, government, and industry. The regulation of the expression and function of N-methylD-aspartate (NMDA) receptors was a major conference topic. Using quantitative immunogold electron microscopy, John Morrison (Mount Sinai University, New York, NY) showed that the number of NR1 subunits of the receptor per synapse increases in the outer molecular layer of the hippocampal dentate gyrus within days after a perforant path transection. This and the demonstration that a similar increase occurs in area CA1 of the hippocampus in old ovariectomized rats provides anatomical evidence for a role of NMDA receptor proliferation in synaptic plasticity. Results from the laboratory of Suzanne Zukin and Michael Bennett (Yeshiva University, New York, NY) demonstrate that protein kinase C (PKC) modulates NMDA receptor trafficking and channel gating. PKC delivers new NMDA receptors to the surface by SNARE-dependent exocytosis. The degree of potentiation of NR1/NR2A receptors is greatest for NR1 splice variants which have the shortest carboxy terminal; these splice variants also exhibit the highest efficiency of insertion at the cell membrane by constitutive exocytosis. Notably, these mechanisms might be exploitable for the development of drugs that affect NMDA receptor function in subtle ways—and only when PKC is up-regulated under certain physiological and pathological conditions. A fundamentally different, novel pharmacological approach to influence NMDA receptors takes advantage of the fact that several endogenous ligands normally regulate receptor function in the brain (Robert Schwarcz, University of Maryland, Baltimore, MD). The actions of glycine, the prototypical coagonist of the NMDA receptor, have been documented most extensively, but sev1 ASPET-Ray Fuller Symposium: “The Neuropharmacology of Glutamate”, October 14–15, 2000, Baltimore, Maryland. Organizing committee: Joseph T. Coyle (Harvard University), Ted M. Dawson (Johns Hopkins University), Jeffrey F. McKelvy (Merck Research Laboratories, La Jolla, CA), and Robert Schwarcz (University of Maryland).