Distinct NMDA receptor subpopulations contribute to long-term potentiationand long-term depression induction

Long-term potentiation (LTP) and long-term depression (LTD) are persistent modifications of synaptic strength that have been implicated in learning, m emory, and neuronal development. Despite their opposing effects, both forms of plasticity can be triggered by the activation of NMDA receptors. One me chanism proposed for this bidirectional response is that the specific patte rns of afferent stimulation producing LTP and LTD activate to different deg rees a uniform receptor population. A second possibility is that these patt erns activate separate receptor subpopulations composed of different NMDA r eceptor (NR) subunits. To test this hypothesis we examined the inhibition o f LTP and LTD by a series of competitive NMDA receptor antagonists that var ied in their affinities for NR2A/B and NR2C/D subunits. The potency for the inhibition of LTP compared with inhibition of LTD varied widely among the agents. Antagonists with higher affinity for NR2A/B subunits relative to NR C/D subunits showed more potent inhibition of LTP than of LTD. D-3-(2-carbo xypiperazine-4-yl)-1-propenyl-1-phosphonic acid, which binds to NR2A/B with very high affinity relative to NR2C/D, showed an similar to 1000-fold high er potency for LTP than for LTD. These results show that distinct subpopula tions of NMDA receptors characterized by different NR2 subunits contribute to the induction mechanisms of potentiation and depression.