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

TitleTranslational control of depression-like behavior via phosphorylation of eukaryotic translation initiation factor 4E.
Publication TypeJournal Article
Year of Publication2018
AuthorsAguilar-Valles A, Haji N, De Gregorio D, Matta-Camacho E, Eslamizade MJ, 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
JournalNat Commun
Volume9
Issue1
Pagination2459
Date Published2018 Jun 25
ISSN2041-1723
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.

DOI10.1038/s41467-018-04883-5
Alternate JournalNat Commun
PubMed ID29941989
PubMed Central IDPMC6018502
Grant ListFND-148423 / / Canadian Health Services Research Foundation (Fondation Canadianne de la Recherche sur les Service de Santé) /