The high variance of AMPA receptor- and NMDA receptor-mediated responses at single hippocampal synapses: Evidence for multiquantal release

Most of our knowledge about transmission at central synapses has been obtained by studying populations of synapses, but some important properties of synapses can be determined only by studying them individually. An important issue is whether a presynaptic action potential causes, at most, a single vesicle to be released, or whether multiquantal transmission is possible. Previous work in the CA1 region has shown that the response to stimulation of a single axon can be highly variable, apparently because it is composed of a variable number of quantal elements (approximate to 5 pA in amplitude). These quantal events have a low coefficient of variation (CV). Because the number of synaptic contacts involved is not known, the response could be because of uniquantal transmission at a varying number of synapses, or to multliquantal transmission at a single synapse. The former predicts that the CV at individual synapses should be small. We have used optical methods to measure the N-methyl-D-aspartate receptor-mediated Ca2+ elevation at single active synapses. Our main finding is that the amplitude of nonfailure responses could be highly variable, having a CV as large as 0.63. In one fortuitous experiment, the optically studied synapse was the only active synapse, and we could therefore measure both its N-methyl-D-aspartate (NMDA) receptor and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated signals. At this synapse, both signals varied over a 10-fold range and were highly correlated. These results strongly suggest that transmission at single CA1 synapses can be multiquantal. Furthermore, the individual quantal response is very far from saturation, allowing the effective summation of many quanta. The existence of multiquantal release has important implications for defining synaptic strength and understanding the mechanisms of synaptic plasticity.