The dynamic range for gain control of NMDA receptor-mediated synaptic transmission at a single synapse

Although the level at which NMDA receptors (NMDARs) are activated can profoundly influence the direction and extent of long-term changes in synaptic strength, the probabilistic nature of quantal release at individual synapses makes it difficult to determine the dynamic operating range of NMDAR-mediated synaptic transmission. By continually driving glutamate release from a single high-fidelity auditory synapse with bursts of high-frequency stimuli, I show here that NMDAR-mediated EPSCs exhibited incremental summation in their amplitude and did not reach a plateau until six or seven consecutive stimuli into the train. An increase in the initial quantal output, by broadening presynaptic spikes with the potassium channel blocker tetraethylammonium (TEA, 0.2 mm), slightly increased the plateau amplitude at 200/300 Hz but shifted its peak temporally toward the earlier stimuli. These results suggest that the plateau amplitude in TEA reflects the activation of the entire population of synaptic NMDARs and hence the maximal gain of NMDAR-mediated synaptic transmission. This maximum was estimated to be 3.2-fold of the basal synaptic strength, giving a 31% occupancy of synaptic NMDARs by glutamate. Thus, synaptic NMDARs possess a broad dynamic range within which the activity-dependent control of synaptic strength and plasticity can potentially be tuned by the amount of Ca(2+) influx associated with different levels of NMDAR occupancy within the same synapse.