Coordinated Activation of AMPA and NMDA Receptor during Quantal Synaptic Transmission

Abstract:
AMPA and NMDA receptors, two subtypes of glutamate receptors that often co-localize at central excitatory synapse, differ markedly in their biophysical properties and physiological functions. Yet, little is known about their coordinated activation during synaptic transmission. We investigated their activation at single synapses using fast synapse-like glutamate applications. Under conditions where both currents could be measured concomitantly, synaptic AMPA and NMDA receptor peak currents co-varied with incremental concentrations of glutamate. Dose-response relationships indicated that both receptors had similar EC ₅₀ . However, their EC ₅₀ differ significantly under longer durations of glutamate applications. A marked covariance of AMPA and NMDA receptor currents was also observed during single synapse evoked synaptic transmission, supporting that both receptors have similar apparent affinities during endogenous transmission. To delineate the possible mechanisms underlying the affinities of AMPA and NMDA receptors, numerical simulations based on previously reported kinetic models for AMPA and NMDA receptor and our experimental kinetic measurements were performed. Results indicated that the similar apparent affinity between the two receptors under fast synaptic-like glutamate transients was dictated by their comparable binding rates, while the low affinity of the NMDA receptor for glutamate under equilibrium conditions was largely determined by the slow dissociation rate. Together, these results suggest that glutamate released from a single vesicle lead to a similar level of AMPA and NMDA receptor activation and is generally insufficient to saturate both AMPA and NMDA receptors. As a result, factors affecting the concentration of glutamate in synaptic cleft can play an important role in determining the strength of synaptic transmission.