title: Two-stage translational control of dentate gyrus LTP consolidation is mediated by sustained BDNF-TrkB signaling to MNK.
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.
authors.affiliation: 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.
authors.forename: Debabrata
authors.initials: D
authors.lastname: Panja
authors.affiliation: Centre for Biological Sciences, Life Sciences Building, Highfield Campus, University of Southampton, Southampton SO17 1BJ, UK.
authors.forename: Justin W
authors.initials: JW
authors.lastname: Kenney
authors.affiliation: Department of Biomedicine and Prevention, University Tor Vergata, 00133 Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: D'Andrea
authors.affiliation: CIR Department, Faculty of Medicine, University Campus Bio-Medico, 00128 Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Zalfa
authors.affiliation: Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway.
authors.forename: Anni
authors.initials: A
authors.lastname: Vedeler
authors.affiliation: 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.
authors.forename: Karin
authors.initials: K
authors.lastname: Wibrand
authors.affiliation: Department of Biochemistry, Osaka University of Pharmaceutical Sciences, Osaka 569-1094, Japan.
authors.forename: Rikiro
authors.initials: R
authors.lastname: Fukunaga
authors.affiliation: Department of Biomedicine and Prevention, University Tor Vergata, 00133 Rome, Italy; VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Center for Human Genetics and Leuven Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven, Belgium.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bagni
authors.affiliation: Centre for Biological Sciences, Life Sciences Building, Highfield Campus, University of Southampton, Southampton SO17 1BJ, UK; South Australian Health and Medical Research Institute, and School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA 5000, Australia.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Proud
authors.affiliation: 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. Electronic address: clive.bramham@biomed.uib.no.
authors.forename: Clive R
authors.initials: CR
authors.lastname: Bramham
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D018891:Dentate Gyrus / Q000378:metabolism*; D004789:Enzyme Activation; D039562:Eukaryotic Initiation Factor-4F / Q000378:metabolism; D039642:Eukaryotic Initiation Factors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism; D017774:Long-Term Potentiation; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D020813:Receptor, trkB / Q000378:metabolism*; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D003598:Cytoskeletal Proteins; D039562:Eukaryotic Initiation Factor-4F; D039642:Eukaryotic Initiation Factors; D048049:Extracellular Signal-Regulated MAP Kinases; D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; D020813:Receptor, trkB; C583882:EIF4EBP2 protein, rat; C092069:activity regulated cytoskeletal-associated protein; C106281:Mknk1 protein, mouse; C491394:Mknk1 protein, rat