Frequency-dependent N-methyl-D-aspartate receptor-mediated synaptic transmission in rat hippocampus.

1. The effects of the N-methyl-D-aspartate (NMDA) antagonist, D-2-amino-5-phosphonovalerate (APV) were examined on synaptic responses evoked by high-frequency stimulation of the Schaffer collateral-commissural pathway, in the presence of Mg2+ (1 or 2 mM) and functional synaptic inhibition. 2. The synaptic response evoked by 100 Hz stimulation comprised fast excitatory postsynaptic potentials (EPSPs) evoked by each shock and a slow depolarization. APV reduced the size of the depolarization without depressing the fast EPSPs. 3. The mean (+/- 1 S.E.) amplitude of the APV-sensitive component (3.0 +/- 0.3 mV), evoked by 100 Hz stimulation at membrane potentials near rest, was invariably smaller than the first fast EPSP (9.8 +/- 0.7 mV). Both of these synaptic components had similar thresholds and increased in amplitude as the stimulus intensity was raised. There was a positive correlation between the amplitude of the two components (r = 0.57, P less than 0.01). 4. The amplitude of the APV-sensitive component was positively correlated (r = 0.97, P less than 0.05) with the frequency of stimulation during the trains (between 10 and 100 Hz). The threshold frequency for evoking an APV-sensitive component was approximately 10 Hz. 5. In contrast to the fast EPSPs the amplitude of the APV-sensitive component increased with depolarization, and decreased with hyperpolarization, of a neurone from its resting membrane potential. The component was no longer present in some cells which had been hyperpolarized sufficiently. 6. It is suggested that during high-frequency stimulation a neurone may become depolarized for a sufficient time to reduce the Mg2+ block of NMDA channels. This enables the NMDA receptor system to contribute transiently to the synaptic response, despite the inhibitory synaptic mechanisms which prevent its activation during single-shock stimulation. The characteristics of the NMDA receptor-mediated synaptic response may explain properties relating to the induction of long-term potentiation (LTP).