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

• DOI: 10.1038/s41467-018-04883-5
• Publication Date: 2018-06-19T10:49:48Z
• Authors: Argel Aguilar-Valles; Nabila Haji; Danilo De Gregorio; Edna Matta-Camacho; Mohammad J. Eslam...; 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
• Keywords: Male; 0301 basic medicine; Science; Anxiety; Citalopram; Biochemistry; Article; Mice; 03 medical and health sciences; NF-KappaB Inhibitor alpha; Fluoxetine; Animals; Phosphorylation; Animals; Antidepressive Agents; Anxiety; Behavior, Animal; Benzofurans; Citalopram; Depression; Depressive Disorder, Major; Eukaryotic Initiation Factor-4E; Female; Fluoxetine; Inflammation; Ketamine; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-KappaB Inhibitor alpha; Phosphorylation; Protein Biosynthesis; Protein-Serine-Threonine Kinases; Serotonin and Noradrenaline Reuptake Inhibitors; Synaptic Transmission; Tumor Necrosis Factor-alpha; Chemistry (all); Biochemistry, Genetics and Molecular Biology (all); Physics and Astronomy (all); Benzofurans; Inflammation; Mice, Knockout; Depressive Disorder, Major; Behavior, Animal; Depression; Q; Antidepressive Agents; Mice, Inbred C57BL; Eukaryotic Initiation Factor-4E; Protein Biosynthesis; Female; Ketamine

AbstractTranslation 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.