Enhancement of long-term depression by soluble amyloid 尾 protein in rat hippocampus is mediated by metabotropic glutamate receptor and involves activation of p38MAPK, STEP and caspase-3

详细信息    查看全文

• 作者：X. Chen ; R. Lin ; L. Chang ; S. Xu ; X. Wei ; J. Zhang ; C. Wang ; R. Anwyl ; Q. Wang
• 关键词：A尾 ; amyloid-尾 protein ; AD ; Alzheimer&rsquo ; s disease ; AMPAR ; a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor ; DHPG ; 3 ; 5-dihydroxyphenylglycine ; EPSP ; excitatory postsynaptic potential ; fEPSPs ; field excitatory postsynaptic potentials ; LTP ; long-term potentiation ; LTD ; long-term depression ; mTOR ; mammalian target of Rapamycin ; mGluRs ; metrabotropic glumate receptors ; NPR ; neuronal pentraxin receptor ; NMDAR ; N-methyl-d-aspartate receptor ; p38MAPK ; p38 mitogen-activated protein kina
• 刊名：Neuroscience
• 出版年：3 December, 2013
• 年：2013
• 卷：253
• 期：Complete
• 页码：435-443
• 全文大小：1065 K

文摘

It is reported that the amyloid-尾 protein (A尾)-induced impairments in synaptic plasticity coincide with memory decline and dementia. Although A尾-induced inhibition of hippocampal long-term potentiation has been intensively investigated, the underlying mechanism of A尾-enhanced long-term depression (LTD) is not clear. Here, we report that acute exposure of rat hippocampal slices to soluble A尾-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尾-enhanced LTD, whereas D-AP5 (a not selective N-methyl-d-aspartate receptor (NMDAR) antagonist) had no effect on A尾-enhanced LTD compared with controls. In addition, A尾-enhanced LTD was occluded by pre-application of 3,5-dihydroxyphenylglycine, a Group1 mGluR (mGluR1/5) agonist, suggesting A尾-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尾 on LTD. Application of striatal-enriched protein tyrosine phosphatase (STEP) activator MG132 facilitated induction of LTD by wLFS, but did not block following A尾-enhanced LTD induced by another wLFS. On the other hand, A尾-enhanced LTD blocked following MG132-LTD by wLFS, suggesting A尾-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尾-enhanced LTD. However, neither the tumor necrosis factor-伪 converting enzyme inhibitor TAPI-2 nor the mammalian target of rapamycin inhibitor rapamycin prevented the enhancement of A尾 on LTD. Therefore, we conclude that soluble A尾 enhances LTD in the hippocampal dentate gyrus region, and the facilitatory effect of A尾 on LTD involves mGluR1/5, p38MAPK, STEP and caspase-3 activation.