1. As part of an effort to evaluate the biological plausibility of theoretically derived principles of synaptic modification, we studied activity-dependent long-term depression (LTD) of glutamatergic transmission in the hippocampus of anesthetized adult rats. Field potentials of CA1 pyramidal cells evoked by single-pulse stimulation (0.1 Hz) of the commissural afferents were recorded before and after paired-pulse stimulation (0.5 Hz) of the same pathway. A train of 150 or 200 paired pulses produced robust LTD of the commissural input to the CA1 pyramidal neurons when the interstimulus interval (ISI) of the pairs was short (25 ms) but not when the ISI was long (1,000 ms). 2. Paired-pulse stimulation with the short but not with the long ISI also was associated with pronounced inhibition of pyramidal cell firing upon the second pulse of a pair, despite the fact that the excitatory input was facilitated with the short-ISI paradigm. The inhibition of pyramidal cell activity was mediated by input to the pyramidal cells from local gamma-aminobutyric acid (GABA)-releasing interneurons activated by commissural fibers and/or CA1 recurrent collaterals, because the inhibition was eliminated by local administration of the selective GABAA receptor antagonist, bicuculline (50 microM), near the recording site. 3. Postsynaptic input from GABAergic interneurons was necessary for the induction of LTD, because short-ISI paired-pulse stimulation failed to produce LTD in the presence of bicuculline. 4. N-methyl-D-aspartate (NMDA) receptor-mediated excitation also was necessary for the induction of LTD, because administration of the selective NMDA receptor antagonist, D-2-amino-5-phosphonvaleric acid (100 microM), near the recording site prevented the development of LTD.(ABSTRACT TRUNCATED AT 250 WORDS)