Presynaptic NMDA Receptors and Spike Timing-Dependent Depression at Cortical Synapses

Abstract

It has recently been discovered that some forms of timing-dependent long-term depression (t-LTD) require presynaptic N-methyl-d-aspartate (NMDA) receptors. In this review, we discuss the evidence for the presence of presynaptic NMDA receptors at cortical synapses and their possible role in the induction of t-LTD. Two basic models emerge for the induction of t-LTD at cortical synapses. In one model, coincident activation of presynaptic NMDA receptors and CB1 receptors mediates t-LTD. In a second model, CB1 receptors are not necessary, and the activation of presynaptic NMDA receptors alone appears to be sufficient for the induction of t-LTD.

Keywords: NMDA; STDP; plasticity; presynaptic mechanisms; t-LTD.

Figure 1

Two models of presynaptic NMDA receptor-dependent t-LTD. Model 1: Presynaptic NMDA receptors and CB1 receptors drive t-LTD. In this model, during post-before-pre pairing, presynaptically released glutamate activates mGluRs and postsynaptic action potentials enhance Ca²⁺ influx. This would lead to endocannabinoid (eCB) synthesis. eCB diffuses retrogradely and binds to presynaptic CB1 receptors. Co-activation of presynaptic CB1 receptors and presynaptic NMDA receptors causes synaptic depression. In this model, presynaptic NMDA receptors are activated by glutamate release from the presynaptic terminal. Astrocytic release of gliotransmitters (glutamate as agonist and/or D-serine or glycine as co-agonist) may contribute to activating neuronal NMDA receptors. Model 2: In a second model, eCB-dependent retrograde signaling is not necessary for induction of t-LTD (dashed crosses), and activation of presynaptic NMDA receptors alone appears to be sufficient to drive presynaptic t-LTD. The source of transmitter activating presynaptic NMDA receptors is unknown.