1. Enhancement of the induction of long-term depression (LTD) of excitatory postsynaptic currents (EPSCs) by a priming stimulus was investigated in the medial perforant pathway of the dentate gyrus of the hippocampus in vitro. 2. In control, LTD could be induced by a conditioning low frequency stimulation (LFS) consisting of sixty, although not thirty or fewer, stimuli at 1 Hz applied at a holding potential of -40 mV. 3. A conditioning LFS of just five stimuli at 1 Hz was found to induce LTD if preceded 1-5 min, but not 15 min, by a priming LFS of five stimuli at 1 Hz, -40 mV, which did not by itself induce LTD. 4. A low concentration of the protein kinase C (PKC) activator (-)-indolactam V, which did not itself induce LTD, reduced the threshold for the number of stimuli inducing LTD following the priming stimulus, while a high concentration of (-)-indolactam V directly induced a depression of the test excitatory postsynaptic current (EPSC), which occluded LFS-induced LTD. This suggests that the priming of LTD and also the direct induction of LTD involves the activation of PKC. 5. The pseudosubstrate peptide inhibitor PKC19-36 inhibited the induction of LTD by the priming protocol and by the control induction conditioning protocol. 6. These experiments demonstrate that a covert synaptic change involving generation of PKC is very effective in producing conditions whereby LTD is induced by very brief synaptic stimulation.