NR3A-containing NMDARs promote neurotransmitter release and spike timing–dependent plasticity

Larsen et al . find that presynaptic NMDA receptors at neocortical synapses are heteromeric receptors containing the developmentally expressed NR3A subunit. Their data also indicate that NR3A-containing presynaptic NMDARs mediate tonic presynaptic activity, synaptic transmission and spike timing–dependent plasticity. Recent evidence suggests that presynaptic-acting NMDA receptors (preNMDARs) are important for neocortical synaptic transmission and plasticity. We found that unique properties of the NR3A subunit enable preNMDARs to enhance spontaneous and evoked glutamate release and that NR3A is required for spike timing–dependent long-term depression in the juvenile mouse visual cortex. In the mature cortex, NR2B-containing preNMDARs enhanced neurotransmission in the absence of magnesium, indicating that presynaptic NMDARs may function under depolarizing conditions throughout life. Our findings indicate that NR3A relieves preNMDARs from the dual-activation requirement of ligand-binding and depolarization; the developmental removal of NR3A limits preNMDAR functionality by restoring this associative property.