Calcium-dependent inactivation of the monosynaptic NMDA EPSCs in rat hippocampal neurons in culture

The effects of increased dendritic calcium concentration ([Ca2+](i)) induce d by single action potentials on monosynaptic glutamatergic excitatory post synaptic currents (EPSCs) were studied in cultured rat hippocampal neurons. To investigate the respective roles of pre- and postsynaptic elements in t he depolarization-induced NMDAR inactivation, we have performed simultaneou s paired whole-cell recordings from monosynaptically connected pre- and pos tsynaptic hippocampal neurons. We report that the single firing of the post synaptic neuron did not result in inactivation of the NMDAR-EPSC, whereas a burst of depolarizing steps transiently depressed the NMDAR-EPSCs in both pyramidal cells and interneurons. This effect was mediated by postsynaptic voltage-gated Ca2+ influx, as it was prevented by: (i) buffering postsynapt ic [Ca2+](i) with 30 mM BAPTA; (ii) removing extracellular Ca2+; or (iii) a pplying Cd-o(2+) (100 mu M), a voltage-gated calcium channel blocker. It do es not involve presynaptic mechanisms as it selectively affected NMDA but n ot alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor-med iated EPSCs. These results suggest that inactivation of NMDAR-channels by v oltage-gated Ca influx is a general property of hippocampal neurons, which may play an important role in reducing postsynaptic NMDAR Ca2+ influx that leads to plasticity or excitotoxicity during sustained neuronal activity.