ATP receptors participate in synaptic transmission and intracellular calcium signaling in the hippocampus by providing a component of the excitatory input to CA1 pyramidal neurons. The activation of P2X purinoreceptors generates calcium influx that does not require cell depolarization, but this response desensitizes at increased rates of stimulation. Here we show that inhibition of P2X receptors dramatically facilitates the induction of long-term potentiation (LTP). High-frequency stimulation (HFS) (1 sec) induced LTP in CA1, whereas brief HFS (0.2 sec) caused only short-term potentiation. However, when P2X receptors were inhibited by PPADS (pyridoxal phosphate-6-azophenyl-2'-4'-disulphonic acid) or desensitized by the nonhydrolyzable ATP analog alpha,beta-methyleneATP, brief HFS reliably induced LTP. Inhibition of P2X receptors had no facilitatory effect on LTP when NMDA receptors were blocked. We hypothesized that P2X receptors affect the threshold for LTP by altering Ca2+-dependent inactivation of NMDA receptors. In isolated pyramidal CA1 neurons and hippocampal slices, activation of P2X receptors did cause inhibition of NMDA receptor-mediated current. We suggest that, by controlling the background calcium and thus the activity of NMDA receptors at low firing frequencies, P2X receptors act as a dynamic low-frequency filter so that weak stimuli do not induce LTP.