Roles of Presynaptic NMDA Receptors in Neurotransmission and Plasticity

Abstract

Presynaptic NMDA receptors (preNMDARs) play pivotal roles in excitatory neurotransmission and synaptic plasticity. They facilitate presynaptic neurotransmitter release and modulate mechanisms controlling synaptic maturation and plasticity during formative periods of brain development. There is an increasing understanding of the roles of preNMDARs in experience-dependent synaptic and circuit-specific computation. In this review we summarize the latest understanding of compartment-specific expression and function of preNMDARs, and how they contribute to synapse-specific and circuit-level information processing.

Keywords: NMDA receptors; cortex; development; synaptic plasticity.

Figure 1. Roles of preNMDARs in synaptic transmission and plasticity

Action potential (AP) arrival at the presynaptic bouton triggers presynaptic release of glutamate that binds to postsynaptic AMPA receptors (AMPAR), NMDA receptors (postNMDARs) and metabotropic glutamate receptors (mGluRs), as well as presynaptic NMDA receptors (preNMDARs). During timing-dependent LTD induction, presynaptically released glutamate activates mGluRs and postsynaptic action potentials enhance Ca²⁺ influx through voltage-gated calcium channels (VGCCs), leading to synthesis of endocannabinoids (eCBs) which diffuse in a retrograde manner and bind to presynaptic and/or astrocytic CB1 receptors. Co-activation of presynaptic CB1 receptors and presynaptic NMDA receptors causes synaptic depression. Alternatively, activation of astrocytic CB1Rs results in astrocytic release of glutamate or d-serine, which activates preNMDARs (see [54]), although in some instances CB1 receptor activation might not be required. Ca²⁺ influx through preNMDAR activates presynaptic calcineurin (CaN), which may play a role in regulating signalling pathways involved in synaptic depression. PreNMDARs can also be activated by glutamate released from the presynaptic terminal causing synaptic self-depression. Glutamate transporters (Glt-1) in astrocytes regulate basal levels of glutamate and may therefore influence tonic preNMDAR activation.

Figure 2. Evidence for the axonal expression of preNMDARs

(a) PreNMDARs are localized to presynaptic boutons as demonstrated by immunogold labelling of the obligatory NMDAR subunit GluN1 in L2/3 of the visual cortex (adapted from [42], scale bar indicates 200 nm). (b) In cultured cortical neurons, the NMDAR subunit GluN1 (NR1) colocalizes with the axonal marker tau-1 (adapted from [67]). (c) In recordings from GABAergic terminals of cultured cerebellar neurons, application of NMDA elicits inward currents that are blocked by the NMDAR antagonist CPP, suggesting these terminals express preNMDARs (adapted from [34]). (d) Pairing action potential firing at 30 Hz with the uncaging of MNI-NMDA near presynaptic boutons produces supralinear calcium responses in a subset of boutons of L5 visual cortical pyramidal neurons (adapted from [23]). This result suggests that a subset of presynaptic boutons express preNMDARs that influence axonal calcium levels and presumably neurotransmitter release. (e) t-LTD at L4-L2/3 synapses requires axonal preNMDARs. Uncaging of the caged NMDAR antagonist cMK-801 over presynaptic axons (but not presynaptic soma or dendrites) prior to the t-LTD induction protocol blocks this form of plasticity (adapted from [78]).

Figure 3. Astrocytic involvement in preNMDAR signalling

(a) During t-LTD induction (pairing), astrocytic calcium transients increase. (b) Blocking this increase in astrocytic calcium signalling by “clamping” astrocyte (green cell) calcium levels during the induction protocol blocks t-LTD induction at neighboring L4-L2/3 cortical synapses (a-b adapted from [54]). (c) In the absence of the GluN2B-selective antagonist ifenprodil, electrical stimulation of astrocytes (AST) increases spontaneous glutamate release onto hippocampal dentate granule cells (washout, right panel). Ifenprodil blocks this increase, suggesting astrocytes influence excitatory neurotransmission at these synapses through interaction with GluN2B subunit-containing preNMDARs (adapted from [68]). (d) In recordings from L5 neurons in the entorhinal cortex, application of the NMDAR co-agonist d-serine does not increase the mEPSC frequency, suggesting preNMDARs in this brain area are saturated with this co-agonist. However, pre-incubation with the glia-specific metabolic inhibitor NFAc reduces baseline mEPSC frequency and allows the application of d-serine to increase mEPSC frequency. Indirectly, this suggests that glial release of the endogenous NMDAR co-agonist d-serine results in the saturation of the preNMDAR co-agonist binding site at L5 entorhinal cortical synapses (adapted from [86]).