Calcium-dependent inactivation of synaptic NMDA receptors in hippocampal neurons

1. We examined whether synaptically activated N-methyl-D-aspartate (NMDA) receptors are regulated by intracellular calcium in cultured hippocampal neurons by comparing excitatory postsynaptic currents (EPSCs) to the previously described calcium-dependent regulation of whole cell NMDA currents. Standard whole cell recording and fast application methods were used. 2. Low-frequency (0.2 Hz) stimulation of EPSCs in the presence of 2-amino-5-phosphonovalerate (AP5) evoked a constant amplitude alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated EPSC. On removal of AP5 in Ca(2+)-containing solutions, the amplitude of the slow NMDA receptor-mediated EPSC decreased by approximately 50% during the next 10 stimuli. The decrease in the EPSC was dependent on the extracellular calcium concentration and stimulus frequency, consistent with Ca(2+)-dependent desensitization/inactivation of postsynaptic NMDA receptors. A whole cell prepulse of NMDA (10 microM, 10 s) in Ca(2+)-containing solutio...