Two-Stage Translational Control of Dentate Gyrus LTP Consolidation Is Mediated by Sustained BDNF-TrkB Signaling to MNK

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. [Display omitted] •Sustained BDNF-TrkB signaling controls LTP consolidation in vivo•TrkB signaling to MNK mediates LTP consolidation•MNK regulates CYFIP1/FMRP translation repressor complex in early-stage LTP•MNK regulates 4E-BP2 and dendritic protein synthesis in late-stage LTP The logic of translational control in synaptic plasticity is not well understood. Panja et al. show that long-term potentiation in the dentate gyrus of live rodents is a two-stage process driven by brain-derived neurotrophic factor signaling to MAP-kinase-interacting kinase and activation of functionally and mechanistically distinct forms of translation.