D-Serine Inhibits Non-ionotropic NMDA Receptor Signaling

NMDA-type glutamate receptors (NMDARs) are widely recognized as master regulators of synaptic plasticity, most notably for driving long-term changes in synapse size and strength that support learning. NMDARs are unique among neurotransmitter receptors in that they require binding of both neurotransmitter (glutamate) and co-agonist (e.g., D-serine) to open the receptor channel, which leads to the influx fl ux of calcium ions that drive synaptic plasticity. Over the past decade, evidence has accumulated that NMDARs also support synaptic plasticity via ion fl ux-independent (non-ionotropic) signaling upon the binding of glutamate in the absence of co-agonist, although conflicting fl icting results have led to significant fi cant controversy. Here, we hypothesized that a major source of contradictory results might be attributed to variable occupancy of the co-agonist binding site under different experimental conditions. To test this hypothesis, we manipulated co-agonist availability in acute hippocampal slices from mice of both sexes. We found that enzymatic scavenging of endogenous co-agonists enhanced the magnitude of long-term depression (LTD) induced by non-ionotropic NMDAR signaling in the presence of the NMDAR pore blocker MK801. Conversely, a saturating concentration of D-serine completely inhibited LTD and spine shrinkage induced by glutamate binding in the presence of MK801 or Mg2+. 2+ . Using a F & ouml;rster resonance energy transfer (FRET)-based assay in cultured neurons, we further found that D-serine completely blocked NMDA-induced conformational movements of the GluN1 cytoplasmic domains in the presence of MK801. Our results support a model in which D-serine availability serves to modulate NMDAR signaling and synaptic plasticity even when the NMDAR is blocked by magnesium.