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

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

Author information

1
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.
2
Centre for Biological Sciences, Life Sciences Building, Highfield Campus, University of Southampton, Southampton SO17 1BJ, UK.
3
Department of Biomedicine and Prevention, University Tor Vergata, 00133 Rome, Italy.
4
CIR Department, Faculty of Medicine, University Campus Bio-Medico, 00128 Rome, Italy.
5
Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway.
6
Department of Biochemistry, Osaka University of Pharmaceutical Sciences, Osaka 569-1094, Japan.
7
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.
8
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.
9
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.

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.

PMID:
25453757
DOI:
10.1016/j.celrep.2014.10.016
[Indexed for MEDLINE]
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