Translational control of depression-like behavior via phosphorylation of eukaryotic translation initiation factor 4E

Argel Aguilar-Valles, Nabila Haji, Danilo De Gregorio, Edna Matta-Camacho, Mohammad J. Eslamizade, Jelena Popic, Vijendra Sharma, Ruifeng Cao, Christoph Rummel, Arnaud Tanti, Shane Wiebe, Nicolas Nuñez, Stefano Comai, Robert Nadon, Giamal Luheshi, Naguib Mechawar, Gustavo Turecki, Jean Claude Lacaille, Gabriella Gobbi, Nahum Sonenberg

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Abstract

Translation of mRNA into protein has a fundamental role in neurodevelopment, plasticity, and memory formation; however, its contribution in the pathophysiology of depressive disorders is not fully understood. We investigated the involvement of MNK1/2 (MAPK-interacting serine/threonine-protein kinase 1 and 2) and their target, eIF4E (eukaryotic initiation factor 4E), in depression-like behavior in mice. Mice carrying a mutation in eIF4E for the MNK1/2 phosphorylation site (Ser209Ala, Eif4e ki/ki), the Mnk1/2 double knockout mice (Mnk1/2 -/-), or mice treated with the MNK1/2 inhibitor, cercosporamide, displayed anxiety-and depression-like behaviors, impaired serotonin-induced excitatory synaptic activity in the prefrontal cortex, and diminished firing of the dorsal raphe neurons. In Eif4e ki/ki mice, brain IκBα, was decreased, while the NF-κB target, TNFα was elevated. TNFα inhibition in Eif4e ki/ki mice rescued, whereas TNFα administration to wild-type mice mimicked the depression-like behaviors and 5-HT synaptic deficits. We conclude that eIF4E phosphorylation modulates depression-like behavior through regulation of inflammatory responses.

Original languageEnglish (US)
Article number2459
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

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    Aguilar-Valles, A., Haji, N., De Gregorio, D., Matta-Camacho, E., Eslamizade, M. J., Popic, J., Sharma, V., Cao, R., Rummel, C., Tanti, A., Wiebe, S., Nuñez, N., Comai, S., Nadon, R., Luheshi, G., Mechawar, N., Turecki, G., Lacaille, J. C., Gobbi, G., & Sonenberg, N. (2018). Translational control of depression-like behavior via phosphorylation of eukaryotic translation initiation factor 4E. Nature communications, 9(1), [2459]. https://doi.org/10.1038/s41467-018-04883-5