We used the low affinity N-methyl-D-aspartate (NMDA) receptor agonist
D-glutamate to study the time course of synaptic activation of NMDA re
ceptors. 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 (EPS
Cs) evoked by autaptic stimulation. The EPSC time course was mimicked
by NMDA receptor currents evoked in outside-out patches by 1-4 ms appl
ications 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 t
he natural neurotransmitter and that the concentration of free transmi
tter is elevated in the cleft for only a few milliseconds after releas
e.