Neuropsin is essential for early processes of memory acquisition and Schaffer collateral long-term potentiation in adult mouse hippocampus in vivo
Neuropsin is essential for early processes of memory acquisition and Schaffer collateral long-term potentiation in adult mouse hippocampus in vivo
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DOI：
10.1113/jphysiol.2005.098715
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发表时间：
2006-02-01
影响因子：
5.5
通讯作者：
Shiosaka, S
中科院分区：
文献类型：
--
作者：
Tamura, H;Ishikawa, Y;Shiosaka, S
长时程增强（LTP）被认为是特别重要的，在获得与校园相关的记忆，部分原因是它发展迅速，持续不确定的时期。细胞外蛋白质水解被认为是通过改变突触的粘附关系从而改变兴奋性突触的形态来促进LTP。在这里，我们报告，neuropsin（NP），细胞外丝氨酸蛋白酶，是至关重要的参与形成的增强效应和海马依赖形式的记忆。NP-敲除小鼠在Morris水迷宫和Y-迷宫中显著受损，并且未能表现出由单次破伤风诱导的早期LTP。增强作用也被削弱或完全阻断的特异性抑制剂或NP的中和单克隆抗体在体内应用。有趣的是，单独的重组（r-）NP，没有强直刺激，引起持久的增强或抑郁症，这取决于所施加的剂量。r-NP引起的增强被封闭的LTP的诱导之前，而θ-突发引起的LTP被封闭的应用程序单独的r-NP，这表明这两种形式的可塑性有一个共同的信号通路。r-NP引起的增强和抑郁增加了AMPA受体GluR 1亚基上不同位点的磷酸化，这些亚基以前与LTP或长期抑郁有关。因此，我们得出结论，NP是必要的LTP的建立，并在记忆获得中有重要的作用。
Long-term potentiation (LTP) is thought to be particularly important in the acquisition of hippocampus-associated memory, in part because it develops quickly and persists for indefinite periods. Extracellular proteolysis has been hypothesized to contribute to LTP by modifying adhesive relations of synapses and thus the morphology of excitatory synapses. Here we report that neuropsin (NP), an extracellular serine protease, is critically involved in the formation of both the potentiation effect and hippocampus-dependent forms of memory. NP-knockout mice were significantly impaired in the Morris water maze and Y-mazes and failed to exhibit early phase LTP induced by a single tetanus. Potentiation was also impaired or completely blocked by in vivo application of a specific inhibitor or a neutralizing monoclonal antibody for NP. Intriguingly, recombinant (r-) NP alone, without tetanic stimulation, elicited either long-lasting potentiation or depression, depending on the applied dose. The r-NP-elicited potentiation was occluded by prior induction of LTP, while theta-burst-elicited LTP was occluded by application of r-NP alone, suggesting that the two forms of plasticity have a common signalling pathway. r-NP-elicited potentiation and depression increased phosphorylation at different sites on the GluR1 subunit of the AMPA receptor that had previously been associated with LTP or long-term depression. Thus, we conclude that NP is necessary for establishment of LTP and has a significant role in memory acquisition.