Dual-component NMDA receptor currents at a single central synapse

Abstract

PRESENT thinking about the way that the NMDA (N-methyl-D-aspartate) class of glutamate receptor operates at central synapses relies mainly on information obtained from single-channel and whole-cell recordings from cultured neurons stimulated by exogenous NMDA receptor agonists^1,2. The mechanisms that operate in the postsynaptic membrane of a normal neuron following release of the natural transmitter are far less clear. An important problem is that most normal neurons receive many excitatory synapses (10³–10⁵ per cell) and these synapses are located on slender dendritic elements far away from the somatic recording site, making the study of discrete synaptic events difficult. Typically, when populations of synapses are activated, NMDA receptor-mediated synaptic potentials appear as slowly rising, long-lasting waves superimposed on faster, non-NMDA-receptor potentials²–⁸. Although believed to be critical for NMDA receptor function^9,10, this slow time-course would not be predicted from single-channel kinetics and its origin remains puzzling. We have now analysed the events occurring at the level of a single excitatory synapse using a simple, small, neuron—the cerebellar granule cell—which has an unusually simple glutamatergic⁸ input. By applying high-resolution whole-cell recording techniques to these cells in situ¹¹, we were able to study the nature of elementary NMDA receptor-mediated synaptic currents. Contrary to expectations, the prominent currents are fast but are followed by slow ones. Both types of current are strongly voltage-dependent but differ subtly in this respect. Furthermore, the currents are absent unless glycine is provided.