ENHANCEMENT OF LONG-TERM DEPRESSION BY SOLUBLE AMYLOID β PROTEIN IN RAT HIPPOCAMPUS IS MEDIATED BY METABOTROPIC GLUTAMATE RECEPTOR AND INVOLVES ACTIVATION OF P38MAPK, STEP AND CASPASE-3

It is reported that the amyloid-beta protein (A beta)-induced impairments in synaptic plasticity coincide with memory decline and dementia. Although A beta-induced inhibition of hippocampal long-term potentiation has been intensively investigated, the underlying mechanism of AD-enhanced long-term depression (LTD) is not clear. Here, we report that acute exposure of rat hippocampal slices to soluble A beta-enhanced LTD induced by weak low-frequency stimulation (wLFS; 1 Hz for 3 min, 180 pulses) in granule cells of the dentate gyrus. Application of LY341495 (a non-selective Group I/II metrabotropic glumate receptor (mGluR) antagonist) completely blocked A beta-enhanced LTD, whereas D-AP5 (a not selective N-methyl-D-aspartate receptor (NMDAR) antagonist) had no effect on A beta-enhanced LTD compared with controls. In addition, A beta-enhanced LTD was occluded by pre-application of 3,5-dihydroxyphenylglycine, a Group1 mGluR (mGluR1/5) agonist, suggesting A beta-enhanced LTD depends on mGluR1/5 but not NMDAR. We also report here that p38 mitogen-activated protein kinase (p38MAPK) inhibitor SB203580 and postsynaptic protein tyrosine phosphatase inhibitors phenylarsine oxide and sodium orthovanadate prevented the facilitatory effect of A beta on LTD. Application of striatal-enriched protein tyrosine phosphatase (STEP) activator MG132 facilitated induction of LTD by wLFS, but did not block following A beta-enhanced LTD induced by another wLFS. On the other hand, A beta-enhanced LTD blocked following MG132-LTD by wLFS, suggesting A beta-enhanced hippocampal LTD involves STEP activation. Application of either non-selective caspase inhibitor Z-VAD-FMK or caspase-3 selective inhibitor Z-DEVD-FMK prevented A beta-enhanced LTD. However, neither the tumor necrosis factor-alpha converting enzyme inhibitor TAPI-2 nor the mammalian target of rapamycin inhibitor rapamycin prevented the enhancement of A beta on LTD. Therefore, we conclude that soluble A beta enhances LTD in the hippocampal dentate gyrus region, and the facilitatory effect of A beta on LTD involves mGluR1/5, p38MAPK, STEP and caspase-3 activation. (C) 2013 IBRO. Published by Elsevier Ltd. All rights reserved.