Panja Debabrata, Kenney Justin W, D'Andrea Laura, Zalfa Francesca, Vedeler Anni, Wibrand Karin, Fukunaga Rikiro, Bagni Claudia, Proud Christopher G, Bramham Clive R
Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway; KG Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, 5009 Bergen, Norway.
Centre for Biological Sciences, Life Sciences Building, Highfield Campus, University of Southampton, Southampton SO17 1BJ, UK.
Cell Rep. 2014 Nov 20;9(4):1430-45. doi: 10.1016/j.celrep.2014.10.016. Epub 2014 Nov 6.
BDNF signaling contributes to protein-synthesis-dependent synaptic plasticity, but the dynamics of TrkB signaling and mechanisms of translation have not been defined. Here, we show that long-term potentiation (LTP) consolidation in the dentate gyrus of live rodents requires sustained (hours) BDNF-TrkB signaling. Surprisingly, this sustained activation maintains an otherwise labile signaling pathway from TrkB to MAP-kinase-interacting kinase (MNK). MNK activity promotes eIF4F translation initiation complex formation and protein synthesis in mechanistically distinct early and late stages. In early-stage translation, MNK triggers release of the CYFIP1/FMRP repressor complex from the 5'-mRNA cap. In late-stage translation, MNK regulates the canonical translational repressor 4E-BP2 in a synapse-compartment-specific manner. This late stage is coupled to MNK-dependent enhanced dendritic mRNA translation. We conclude that LTP consolidation in the dentate gyrus is mediated by sustained BDNF signaling to MNK and MNK-dependent regulation of translation in two functionally and mechanistically distinct stages.
脑源性神经营养因子（BDNF）信号传导有助于蛋白质合成依赖性的突触可塑性，但TrkB信号传导的动力学和翻译机制尚未明确。在此，我们表明，活体啮齿动物齿状回中的长时程增强（LTP）巩固需要持续（数小时）的BDNF-TrkB信号传导。令人惊讶的是，这种持续激活维持了一条从TrkB到丝裂原活化蛋白激酶相互作用激酶（MNK）的原本不稳定的信号通路。MNK活性在机制上不同的早期和晚期促进eIF4F翻译起始复合物的形成和蛋白质合成。在早期翻译中，MNK触发CYFIP1/FMRP阻遏复合物从5'-mRNA帽释放。在晚期翻译中，MNK以突触区室特异性方式调节经典翻译阻遏物4E-BP2。这个晚期阶段与MNK依赖性增强的树突状mRNA翻译相关。我们得出结论，齿状回中的LTP巩固是由BDNF向MNK的持续信号传导以及MNK在两个功能和机制上不同阶段对翻译的依赖性调节介导的。
