Involvement of the p75NTR Signaling Pathway in Persistent Synaptic Suppression Coupled With Synapse Elimination Following Repeated Long-Term Depression Induction
Involvement of the p75NTR Signaling Pathway in Persistent Synaptic Suppression Coupled With Synapse Elimination Following Repeated Long-Term Depression Induction
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DOI：
10.1002/jnr.22505
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发表时间：
2010-12-01
影响因子：
4.2
通讯作者：
Ogura, Akihiko
中科院分区：
文献类型：
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作者：
Egashira, Yoshihiro;Tanaka, Tsunehiro;Ogura, Akihiko
突触可塑性，特别是结构可塑性，被认为是持久记忆的基础。我们以前报道，在大鼠海马切片培养，反复诱导长期抑郁症（LTD）的应用代谢型谷氨酸受体（mGluR）激动剂导致缓慢发展，持久的突触抑制加上突触消除。我们把这种现象称为LOSS（LTD重复操作的突触抑制），以区别于传统的单一LTD，并提出它作为分析结构可塑性的模型。近年来，神经营养素原激活的p75（NTR）信号作为调节神经元凋亡和突触可塑性的可能途径而受到关注。在这项研究中，我们研究了这种信号是否在LOSS的建立中发挥作用。茴香霉素的应用表明，对于LOSS的发生，需要在诱导mGluR依赖性LTD后6小时内合成新的蛋白质，这表明LOSS是一个活跃的过程，因此不是由于营养因子短缺引起的枯萎。此外，我们发现，前BDNF（一种proneurotrophins）是新合成的6小时内诱导LTD。因此，我们外源性应用抗裂解形式的前BDNF，发现突触抑制类似于LOSS。LOSS可以通过在重复LTD诱导后应用结合并中和p75（NTR）的抗体来消除。这些结果表明，参与的p75（NTR）信号通路的持续递减形式的突触可塑性。(C)2010 Wiley-Liss，Inc.
Synaptic plasticity, especially structural plasticity, is thought to be a basis for long-lasting memory. We previously reported that, in rat hippocampus slice cultures, repeated induction of long-term depression (LTD) by application of a metabotropic glutamate receptor (mGluR) agonist led to slowly developing, long-lasting synaptic suppression coupled with synapse elimination. We referred to this phenomenon as LOSS (LTD-repetition-operated synaptic suppression) to discriminate it from conventional single LTD and proposed it as a model for analyzing structural plasticity. Recently, proneurotrophin-activated p75(NTR) signaling has been gaining attention as a possible pathway for the regulation of both neuronal apoptosis and synaptic plasticity. In this study, we examined whether this signaling has a role in the establishment of LOSS. The application of anisomycin indicated that, for LOSS to occur, novel protein synthesis is needed within 6 hr after the induction of mGluR-dependent LTD, which demonstrates that LOSS is an active process and therefore is not due to withering in response to a shortage of trophic factors. Furthermore, we found that pro-BDNF (a species of proneurotrophins) is newly synthesized within 6 hr after the induction of LTD. We therefore exogenously applied a cleavage-resistant form of pro-BDNF, finding synaptic suppression similar to LOSS. LOSS could be abolished by the application of an antibody that binds to and neutralizes p75(NTR) following repeated LTD induction. These results suggest involvement of the p75(NTR) signaling pathway in the for g-lasting decremental form of synaptic plasticity. (C) 2010 Wiley-Liss, Inc.