We used the low affinity N-methyl-d-aspartate (NMDA) receptor agonist d-glutamate to study the time course of synaptic activation of NMDA receptors. Repetitive stimulation of cultured hippocampal neurons loaded with d-glutamate caused a dramatic shortening of both the rising and decaying phases of NMDA receptor excitatory postsynaptic currents (EPSCs) evoked by autaptic stimulation. The EPSC time course was mimicked by NMDA receptor currents evoked in outside-out patches by 1-4 ms applications of d-glutamate Thus, d-glutamate can be released as a false transmitter. The results show that both the rise and fall of the NMDA receptor EPSCs are normally controlled by the slow unbinding rate of the natural neurotransmitter and that the concentration of free transmitter is elevated in the cleft for only a few milliseconds after release.
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