Objective:To observe oxygen/glucose deprivation (OGD) induced long-term depression (LTD) during synaptic transmission at mossy fiber to CA3 (MF-CA3) synapses and to study the underlying mechanisms. Methods: Sprague Dawley (SD) newborn rats of 2-3 weeks after birth were selected for hippocampal slices. We performed whole-cell patch-clamp recording on CA3 pyramidal neurons and monitored evoked excitatory postsynaptic currents (EPSCs) at MF-CA3 synapses upon mossy fiber stimulation. After 15-min of OGD, we observed the changes of synaptic transmission. We also co-applied blockers of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs, which blocked by kynurenic acid), metabotropic glutamate receptors (mGluRs, which blocked by LY341495) or calcium chelator during OGD treatment to examine whether OGD-induced alteration in synaptic transmission requires activation of these receptors or increase of calcium. Results:①15-min OGD induced LTD of AMPA receptor (AMPAR)-mediated synaptic transmission at MF-CA3 synapses. ②OGD-induced LTD of AMPAR-mediated responses was dependent on activation of mGluRs but not of AMPARs. ③Removal of Ca2+ from ACSF during OGD or inclusion of Ca2+ chelator BAPTA to the patch pipette solution abolished LTD. Conclusion: OGD induces LTD of AMPAR-mediated synaptic responses at MF-CA3 synapses. This synaptic plasticity requires activation of mGluRs and intracellular Ca2+ increase without AMPARs.