Neurotransmitter is released synchronously and asynchronously following an action potential. Our recent study indicates that the release sites of these two phases are segregated within an active zone, with asynchronous release sites enriched near the center in mouse hippocampal synapses. Here we demonstrate that synchronous and asynchronous release sites are aligned with AMPA receptor and NMDA receptor clusters, respectively. Computational simulations indicate that this spatial and temporal arrangement of release can lead to maximal membrane depolarization through AMPA receptors, alleviating the pore-blocking magnesium leading to greater activation of NMDA receptors. Together, these results suggest that release sites are likely organized to activate NMDA receptors efficiently.

Neurotransmitter is released synchronously and asynchronously following an action potential.The release sites of these two phases are segregated within an active zone, with asynchronous release sites enriched near the center. Here we demonstrate that synchronous and asynchronous release sites are aligned with AMPA receptor and NMDA receptor clusters, respectively.Computational simulations indicate that this spatial and temporal arrangement of release ensures maximal membrane depolarization through AMPA receptors, alleviating the pore-blocking magnesium leading to greater activation of NMDA receptors. Together, these results suggest that release sites are organized to efficiently activate NMDA receptors.3 MainNeurotransmitter is released synchronously within a millisecond of an action potential and asynchronously several milliseconds later 1 . Both phases of release result from exocytosis of synaptic vesicles at a specialized membrane domain: the active zone 2 . Within the active zone lie one or more release sites, individual units at which a single synaptic vesicle may fuse 3 . Our recent study suggests that release sites for synchronous and asynchronous release occupy unique domains within an active zone: synchronous release sites are uniformly distributed, while asynchronous release sites are abundant near the center of an active zone 4 . However, the functional importance of this spatial organization is unknown.A large body of work suggests that location of release is important for the activation of receptors. For excitatory signaling in the central nervous system, glutamate released from presynaptic boutons activates receptors on the postsynaptic membrane. Two ionotropic receptors are critical: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and Nmethyl-D-aspartate (NMDA) receptors 5,6 . Given the low sensitivity of these receptors for glutamate binding 7,8,9,10 , the activation of receptors requires a high concentration of glutamate in the synaptic cleft, which is only achieved at the point of release due to rapid diffusion of glutamate 11,12,13 . In fact, recent studies demonstrate that release sites are aligned with clusters of AMPA receptors 14 , and their association through trans-synaptic adhesion proteins affects the magnitude of synaptic transmission 15 . Thus, where glutamate is released relative to receptors is important for their activation.The timing of glutamate release is also a key component for activation, particularly of the NMDA receptors. NMDA receptors require binding of two glutamate molecules for the activation 16,17 . Depending on the concentration of glutamate, only single binding site may be

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