Distinct NMDA Receptor Pools Determine Diverse Forms of Cortical Plasticity

SUMMARY NMDA receptors (NMDARs) are well-established as coincidence detectors in Hebbian learning, but this requires postsynaptic localization. Presynaptic NMDARs, however, remain controversial due to limitations of pharmacology and calcium imaging. We therefore dissected the function of distinct NMDAR pools using more direct techniques, including immunogold EM, sparse genetic deletion, and paired recordings from layer-5 (L5) pyramidal cell (PC) synapses in mouse primary visual cortex (V1). We found that pre- but not postsynaptic NMDARs regulate both spontaneous and evoked neurotransmitter release. In spike-timing-dependent plasticity, we uncovered a double dissociation: timing-dependent long-term depression (tLTD) requires pre- but not postsynaptic NMDARs, whereas timing-dependent long-term potentiation (tLTP) needs post- but not presynaptic NMDARs. Postsynaptic NMDAR loss also caused developmentally delayed dendritic spine loss and altered axonal and dendritic architecture. In summary, NMDARs do not act as a unified plasticity signal but rather confer location-specific control over diverse forms of synaptic signaling, plasticity, and circuit structure.