The role of zinc, an endogenous N-methyl-d-aspartate (NMDA) receptor antagonist, in long-term potentiation (LTP) at hippocampal CA1 synapses is poorly understood. In the present study, the effect of exogenous zinc and zinc chelators on CA1 LTP was examined by using hippocampal slices from rats. CA1 LTP after tetanic stimulation (100 Hz, 1 s) was potentiated in the presence of 5 microM ZnCl(2), but not in the presence of 30 microM. In varying the frequency (10-100 Hz, 1 s), zinc (5 microM) caused a significant shift of the frequency-response curve and lowered the threshold in LTP induction. The present study is the first to demonstrate that CA1 LTP is potentiated by low micromolar concentrations of zinc. Endogenous zinc is likely to reach low micromolar concentrations in the extracellular compartment in CA1 LTP induction. On the other hand, zinc has no effect on field excitatory postsynaptic potentials (fEPSPs) after tetanic stimulation in the presence of 2-amino-5-phosphonovalerate (APV), an NMDA receptor antagonist, in which LTP was abolished, indicating that NMDA receptor activation is necessary for the potentiation of CA1 LTP by zinc. The pretreatment with ZnAF-2DA, a membrane-permeable zinc chelator, which was used to block the increase in intracellular Zn(2+), inhibited LTP and also LTP potentiated by zinc. It is likely that Zn(2+) taken up during LTP induction potentiates CA1 LTP via NMDA receptor activation.