Subunit-specific NMDA receptor trafficking to synapses.

To elucidate mechanisms controlling the number and subunit composition of synaptic NMDA-Rs in hippocampal slice neurons, the NR1, NR2A, and NR2B subunits were optically and electrophysiologically tagged. The NR2 subunit directs delivery of receptors to synapses with different rules controlling NR2A and NR2B. Synaptic incorporation of NR2B-containing receptors is not limited by synaptic transmission nor enhanced by increased subunit expression. NR2A-containing receptors whose expression normally increases with age replace synaptic NR2B-containing receptors. Replacement is enhanced by increased NR2A expression and requires synaptic activity. Surprisingly, spontaneously released transmitter acting on synaptic NMDA-Rs is sufficient for replacement and reduces NMDA-R responses. Thus, as with AMPA-Rs, synaptic trafficking of NMDA-Rs is tightly regulated and has subunit-specific rules with functionally important consequences.