Metabotropic NMDA receptor function is required for NMDA receptor-dependent long-term depression

NMDA receptor (NMDAR) activation controls long-term potentiation (LTP) as well as long-term depression (LTD) of synaptic transmission, cellular models of learning and memory. A long-standing view proposes that a high level of Ca2+ entry through NMDARs triggers LTP; lower Ca2+ entry triggers LTD. Here we show that ligand binding to NMDARs is sufficient to induce LTD; neither ion flow through NMDARs nor Ca2+ rise is required. However, basal levels of Ca2+ are permissively required. Lowering, but not maintaining, basal Ca2+ levels with Ca2+ chelators blocks LTD and drives strong synaptic potentiation, indicating that basal Ca2+ levels control NMDAR-dependent LTD and basal synaptic transmission. Our findings indicate that metabotropic actions of NMDARs can weaken active synapses without raising postsynaptic calcium, thereby revising and expanding the mechanisms controlling synaptic plasticity.