Gary Lynch

Recent studies have uncovered a synaptic process with properties required for an intermediate step in memory storage. Calcium rapidly and irreversibly increases the number of receptors for glutamate (a probable neurotransmitter) in forebrain synaptic membranes by activating a proteinase (calpain) that degrades fodrin, a spectrin-like protein. This process provides a means through which physiological activity could produce long-lasting changes in synaptic chemistry and ultrastructure. Since the process is only poorly represented in the brain stem, it is hypothesized to be responsible for those forms of memory localized in the telencephalon.

Membranes from rat telencephalon contain a single class of strychnine-insensitive glycine sites. That these sites are associated with N-methyl-D-aspartic acid (NMDA) receptors is indicated by the observations that [3H]glycine binding is selectively modulated by NMDA receptor ligands and, conversely, that several amino acids interacting with the glycine sites increase [3H]N-[1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP) binding to the phencyclidine site of the NMDA receptor. The endogenous compound kynurenate and several related quinoline and quinoxaline derivatives inhibit glycine binding with affinities that are much higher than their affinities for glutamate binding sites. In contrast to glycine, kynurenate-type compounds inhibit [3H]TCP binding and thus are suggested to form a novel class of antagonists of the NMDA receptor acting through the glycine site. These results suggest the existence of a dual and opposite modulation of NMDA receptors by endogenous ligands.