THE EFFECTS OF D-ALPHA-AMINOADIPIC ACID ON LONG-TERM POTENTIATION IN THE HIPPOCAMPUS OF THE RAT IN-VITRO

Many studies on long-term potentiation (LTP) in hippocampal region CA1 focus on receptor-mediated events that are often presumed to be linke d to postsynaptic processes. Whereas it is now well-known that LTP con sists of multiple components involving increases in postsynaptic respo nsiveness as well as enhanced presynaptic release of transmitter, litt le specific information has accrued on the nature of the presynaptic r eceptor-linked events. In the course of a series of experiments examin ing the actions of several antagonists of N-methyl-D-aspartate (NMDA) receptors on LTP, we made certain observations that suggested the role of a novel type of amino acid receptor which possibly was located pre synaptically and that seemed to contribute to the induction of LTP. LT P evoked in region CA1 following high frequency stimulation (HFS) of t he Schaffer collateral-commissural pathway measured 20-30 min after HF S always was attenuated incompletely when induced during administratio n of D alpha AA at doses ranging from 50 mu M to as high as 1000 mu M, whereas 2-amino-5-phosphonopropionate (AP5), at a concentration of 30 mu M, always abolished the process completely. 6,7-Dinitroquinoxaline -2,3-dione (DNQX) (10 mu M) administered alone also did not block LTP completely unless delivered in combination with D alpha AA. These non- APS-like effects of D alpha AA could not be attributed to incomplete a ntagonism of postsynaptic NMDA receptors, since D alpha AA (200 mu M) completely and reversibly blocked the membrane depolarising effects of NMDA, as assessed through intracellular recording. Furthermore, the p harmacologically isolated NMDA-receptor-mediated component of the low- frequency, stimulus-evoked synaptic response was always abolished reve rsibly by D alpha AA (200 mu M). The most parsimonious explanation of these data is that a receptor which is only activated during HFS, is s ensitive to the antagonising actions of AP5 and possibly also to DNQX but not to D alpha AA, and which could conceivably exist on terminals of the Schaffer collateral-commissural fibres, makes a significant con tribution to LTP.