Two-stage translational control of dentate gyrus LTP consolidation is mediated by sustained BDNF-TrkB signaling to MNK

Cell Rep. 2014 Nov 20;9(4):1430-45. doi: 10.1016/j.celrep.2014.10.016. Epub 2014 Nov 6.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Cytoskeletal Proteins / metabolism
  • Dentate Gyrus / metabolism*
  • Enzyme Activation
  • Eukaryotic Initiation Factor-4F / metabolism
  • Eukaryotic Initiation Factors / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fragile X Mental Retardation Protein / metabolism
  • Long-Term Potentiation*
  • Mice, Knockout
  • Nerve Tissue Proteins / metabolism
  • Polyribosomes / metabolism
  • Protein Biosynthesis*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Rats
  • Receptor, trkB / metabolism*
  • Signal Transduction*
  • Synapses / metabolism

Substances

  • Brain-Derived Neurotrophic Factor
  • Cytoskeletal Proteins
  • EIF4EBP2 protein, rat
  • Eukaryotic Initiation Factor-4F
  • Eukaryotic Initiation Factors
  • Nerve Tissue Proteins
  • activity regulated cytoskeletal-associated protein
  • Fragile X Mental Retardation Protein
  • Mknk1 protein, mouse
  • Mknk1 protein, rat
  • Receptor, trkB
  • Protein-Serine-Threonine Kinases
  • Extracellular Signal-Regulated MAP Kinases