Accumulation of amyloid beta (Aβ) protein is a key pathogenic element of Alzheimers disease.It is reported that the Aβ-induced impairments in synaptic plasticity (LTP and LTD) coincides with memory decline and dementia.Although Aβ-induced inhibition of hippocampal long-term potentiation (LTP) has been intensively investigated, the underlying mechanism of Aβ-enhanced long-term depression (LTD) is not clear.Here, we report that acute exposure of rat hippocampal slices to soluble Aβ enhances LTD induced by sub-threshold low frequency stimulation (1 Hz for 3 min, 180 pulses) in granule cells of dentate gyrus.Application of LY341495 (a non-selective Group Ⅰ/Ⅱ mGluR antagonist) completely block Aβ-enhanced LTD, whereas D-AP5 (a not selective NMDAR antagonist) has no effect on Aβ-enhanced LTD compared with untreated controls.In addition, Aβ-enhanced LTD is occluded by pre-application of 5-dihydroxyphenylglycine (DHPG), a Groupl mGluR (mGluR1/5)agonist, suggesting Aβ-enhanced LTD depends on mGluR1/5 but not NMDAR.We also report here that p38mitogen-activated protein kinase (p38MAPK) inhibitor SB203580 and postsynaptic protein tyrosine phosphatase (PTP) inhibitors phenylarsine oxide (PAO) and sodium orthovanadate prevent the inhibitory effect of Aβ on LTD.The possible PTPs involved in Aβ-enhanced LTD could be striatal-enriched protein tyrosine phosphatase (STEP) because Aβ-enhanced LTD occludes a small LTD induced by STEP activator MG132 alone.Application of either non-selective caspase inhibitor Z-VAD-FMK or caspase-3 selective inhibitor Z-DEVD-FMK prevents Aβ-enhanced LTD, suggesting capase-3 is also necessary for the facilitatory effect of Aβ on LTD.However, neither tumor necrosis factor-α converting enzyme (TACE) inhibitor TAPI-2 nor mammalian target of Rapamycin (mTOR)inhibitor Rapamycin prevents the enhancement of Aβ on LTD.Therefore, we conclude that soluble Aβ enhances LTD in hippocampal dentate gyrus region, and the facilitatory effect of Aβ on LTD depends on mGluR1/5,p38MAPK, STEP and caspase-3 activation.