Although late-phase long-term potentiation (L-LTP) is implicated in long-term memory, its molecular mechanisms are largely unknown. Here we provide evidence that L-LTP can be divided into two stages: an induction stage (I) and a maintenance stage (II). Both stages require mature brain-derived neurotrophic factor (mBDNF), but involve distinct underlying mechanisms. Stage I requires secretion of existing proBDNF followed by extracellular cleavage by tPA/plasmin. Stage II depends on newly synthesized BDNF. Surprisingly, mBDNF at stage II is derived from intracellular cleavage of proBDNF by furin/PC1. Moreover, stage I involves BDNF-TrkB signaling mainly through MAP kinase, whereas all three signaling pathways (phospholipase C-γ, PI3 kinase, and MAP kinase) are required for the maintenance of L-LTP at stage II. These results reveal the molecular basis for two temporally distinct stages in L-LTP, and provide insights on how BDNF modulates this long-lasting synaptic alternation at two critical time windows.

尽管晚期长期增强（L-LTP）与长期记忆有关，但其分子机制在很大程度上尚不清楚。在这里，我们提供的证据表明，L-LTP可以分为两个阶段：诱导阶段（I）和维护阶段（II）。这两个阶段都需要成熟的脑源性神经营养因子（mBDNF），但涉及不同的潜在机制。第一阶段需要分泌现有的proBDNF，然后通过tPA /纤溶酶进行细胞外切割。第二阶段依赖于新合成的BDNF。出人意料的是，II期的mBDNF源自弗林蛋白酶/ PC1对proBDNF的细胞内裂解。此外，第一阶段主要通过MAP激酶涉及BDNF-TrkB信号传导，而在第三阶段维持L-LTP则需要所有三个信号传导途径（磷脂酶C-γ，PI3激酶和MAP激酶）。