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 and Nahum Sonenberg ()
Additional contact information
Argel Aguilar-Valles: McGill University
Nabila Haji: Université de Montréal
Danilo De Gregorio: McGill University
Edna Matta-Camacho: McGill University
Mohammad J. Eslamizade: McGill University
Jelena Popic: McGill University
Vijendra Sharma: McGill University
Ruifeng Cao: McGill University
Christoph Rummel: Justus-Liebig-University Giessen
Arnaud Tanti: McGill University
Shane Wiebe: McGill University
Nicolas Nuñez: McGill University
Stefano Comai: McGill University
Robert Nadon: McGill University and Genome Quebec Innovation Centre
Giamal Luheshi: McGill University
Naguib Mechawar: McGill University
Gustavo Turecki: McGill University
Jean-Claude Lacaille: Université de Montréal
Gabriella Gobbi: McGill University
Nahum Sonenberg: McGill University

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04883-5

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