Enhancement of glutamate release uncovers spillover-mediated transmission by N-methyl-D-aspartate receptors in the rat hippocampus

Properties of excitatory postsynaptic currents during increased glutamate r elease were investigated by means of a whole-cell voltage-clamp in CA1 pyra midal neurons of rat hippocampal slices. Enhancement of transmitter release by 50 mu M 4-aminopyridine or by elevated extracellular Ca2+ (up to 5 mM) resulted in a substantial increase in the peak excitatory postsynaptic curr ent amplitude and in the significant stimulus-dependent prolongation of the excitatory postsynaptic current decay. The stronger the stimulus, the slow er the excitatory postsynaptic current decay became. The pharmacologically isolated N-methyl-D-aspartate, but not alpha-amino-3-hydroxy-5-methyl-4-iso xazolepropionic acid component of the excitatory postsynaptic current exhib ited this phenomenon. The possible connection of such behaviour of the N-me thyl-D-aspartate component to the loss of voltage control was tested in the following way: the peak of the N-methyl-D-aspartate component was enhanced under 50 mu M 4-aminopyridine and then returned back to the control level by a low dose of D-2-amino-5-phosphonopentanoic acid. However, the decay of the decreased N-methyl-D-aspartate component remained slow suggesting anot her origin of the stimulus-dependent kinetics. Dihydrokainate, a non-compet itive inhibitor of glutamate uptake, did not influence the kinetics of the N-methyl-D-aspartate component in control but induced its dramatic stimulus -dependent prolongation when applied on the background of a low dose of 4-a minopyridine (10 mu M) which did not affect the decay by itself. We propose that the delayed stimulus-dependent kinetics of the N-methyl-D-a spartate component is due to the saturation of uptake mechanisms and subseq uent activation of extrasynaptic N-methyl-D-aspartate receptors. Our presen t observations therefore support the hypothesis that iv-methyl-D-aspartate receptors may play a role in the cross-talk between synapses by means of th e transmitter spillover. (C) 1999 IBRO. Published by Elsevier Science Ltd.