The biophysical properties of N-methyl-d-aspartate (NMDA) receptor-mediated conductances have been well described, but the means by which NMDA receptors are synaptically activated under physiological conditions remain unclear. Activation of NMDA receptors in the CA1 region of the rat hippocampus by paired and multiple stimuli occurred here with orthodromic stimulation at 10 Hz. Elevating extracellular potassium ion concentration ([K+]o) to 7.5 mM selectively enhanced the NMDA receptor-mediated component of the response to repetitive stimulation, and led to burst-firing of pyramidal cells. The effects of elevated [K+]o on NMDA receptor activation were accompanied by relatively small changes in resting potential, however, and may in part result from a decrease in the potassium equilibrium potential producing slowed repolarization. Supporting this hypothesis, low concentrations of the K+-channel blocker tetraethylammonium added to normal [K+]o solution slowed repolarization and reproduced the effects of elevated [K+]o on NMDA receptor activation. Significant changes in [K+]o occur with neuronal activity in the central nervous system, and thus may play a role in regulating NMDA receptor-mediated postsynaptic activity.
