Long-term depression (LTD) of synaptic strength is induced by glutamate-triggered increases in postsynaptic [Ca2+], through either influx or release from intracellular stores. Induction of LTD has also been reported to require release of Ca2+ from presynaptic stores and activation of presynaptic Ca2+/calmodulin-dependent protein kinase II. This finding leads to the hypothesis that the intercellular messenger nitric oxide (NO) may be a means by which postsynaptic Ca2+ triggers changes expressing LTD in presynaptic terminals. We report that bath application of the oxadiazoloquinoxalone derivative ODQ (4 microM), a selective inhibitor of NO-sensitive guanylyl cyclase (NOGC), markedly attenuated (90%) the magnitude of LTD induced by low-frequency stimulation (LFS; 1 Hz/15 min) of Schaffer collateral-CA1 synapses in hippocampal slices in vitro. Both the NO donor S-nitroso-N-acetylpenicillamine (100 microM) and the membrane-permeant cyclic guanine 3',5'-monophosphate (cGMP) analogue 8-(-4-chlorophenylthio) guanosine (8-pCPT)-cGMP (50 microM) enhanced the magnitude of LTD, which is consistent with he hypothesis that activation of NOGC plays a role in the induction of LTD. Nicotinamide (20 mM), an inhibitor of NO-activated ADP ribosyltransferase, did not impair the induction of LTD. In contrast to de novo LTD, the reversal of long-term potentiation by LFS (depotentiation) was only partially blocked (55%) by ODQ, and heterosynaptic LTD was not impaired at all, suggesting that there are both NOGC-dependent and -independent forms of LTD. Because postsynaptic intracellular infusion of ODQ (500 microM) failed to block the induction of LTD, we conclude that activation of presynaptic NOGC is a necessary step in the induction of an NOGC-dependent component of LTD.