N-Methyl-D-aspartate (NMDA) receptor activation initiates both homosynaptic long-term depression (LTD) and long-term potentiation (LTP) in the CA1 region of the hippocampus. The mechanism by which two opposing forms of synaptic plasticity can be initiated through the activation of a single receptor is not known. We examined the effects of two competitive antagonists on the induction of LTP and LTD, D-2-amino-5-phosphonovaleric acid (D-AP5), a broad spectrum inhibitor of the NMDA receptor, and 3-((RS)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), an antagonist that binds with high affinity to conventional NMDA receptors subtypes, but not to atypical subtypes that are relatively independent of voltage-dependent Mg2+-blockade. As has previously been reported, LTP, LTD, and depotentiation were all blocked by applications of D-AP5. In contrast, only LTP, but not LTD or depotentiation, was blocked by CPP. These observations suggest that decreases and increases of synaptic strength are mediated by the activation of distinct NMDA receptor subpopulations.