Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science 304:1021–1024

Activation of N-methyl-D-aspartate subtype glutamate receptors (NMDARs) is required for long-term potentiation (LTP) and long-term depression (LTD) of excitatory synaptic transmission at hippocampal CA1 synapses, the proposed cellular substrates of learning and memory. However, little is known about how activation of NMDARs leads to these two opposing forms of synaptic plasticity. Using hippocampal slice preparations, we showed that selectively blocking NMDARs that contain the NR2B subunit abolishes the induction of LTD but not LTP. In contrast, preferential inhibition of NR2A-containing NMDARs prevents the induction of LTP without affecting LTD production. These results demonstrate that distinct NMDAR subunits are critical factors that determine the polarity of synaptic plasticity. The molecular mechanisms underlying activity-dependent modification of synaptic strength have been under intensive investigation because of their fundamental importance in brain function and dysfunction (1, 2). Homosynaptic long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission mediated by ␣-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid subtype glutamate receptors (AMPARs) at Schaffer collateral-CA1 synapses of the hippocampus are by far the best-characterized cellular models of synaptic plasticity. Both LTP and LTD require N-methyl-D-aspartate subtype glutamate receptor (NMDAR) activation (1, 3). However, the detailed mechanisms by which the activation of the same class of receptor can produce two opposing forms of synaptic modification remain unclear. A long-held belief has been that the degree of NMDAR activation, and hence the level of postsynaptic calcium elevation during the induction period, dictates the direction of NMDAR-dependent synaptic modification. The strongest evidence for this hypothesis comes from the conversion of LTP to LTD by a partial blockade of NMDARs with low concentrations of the NMDAR antagonist D,L-2-amino-5-phosphophonovaleric acid (APV) (4, 5 ). NMDARs are assembled from NMDAR subunit 1 (NR1) and at least one type of NR2 subunit (6). In the adult rat hippocampus, NR2A and NR2B are the predominant NR2 subunits We first investigated the effect of blocking NR2B-containing NMDARs on LTP and LTD of CA1 field excitatory postsynaptic potentials (fEPSPs) induced by high-and low-frequency stimulation (HFS and LFS), respectively (15). The NR2B subunitselective antagonist ifenprodil (3 M) (16) completely abolished the induction of LTD by LFS, suggesting that LTD requires the activation of NR2B-containing NMDARs It is unlikely that the selective blockade of LTD by NR2B-specific antagonists is due merely to a partial inhibition of NMDARs, because LTP rather than LTD is more sensitive to the partial NMDAR blockade produced by low concentrations of APV (4, 5). To rule out such a possibility, we tested the effect of low-dose APV that generated a partial blockade of NMDAR-mediated excitatory postsynaptic currents (EPSCs) similar to that produced by NR2B antagonist