Format

Send to

Choose Destination
Nat Commun. 2018 Jun 25;9(1):2459. doi: 10.1038/s41467-018-04883-5.

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

Author information

1
Department of Biochemistry and Goodman Cancer Centre, McGill University, Montreal, QC, H3A 1A3, Canada.
2
Department of Neurosciences and Groupe de Recherche sur le Système Nerveux Central (GRSNC), Université de Montréal, Montreal, QC, H3A 1A1, Canada.
3
Department of Psychiatry, McGill University, Montreal, QC, H3C 3J7, Canada.
4
Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, 55812, USA.
5
Institute of Veterinary Physiology and Biochemistry, Justus-Liebig-University Giessen, Giessen, D-35392, Germany.
6
Douglas Mental Health University Institute, McGill University, Montreal, QC, H4H 1R3, Canada.
7
Faculty of Medicine, Vita-Salute San Raffaele University, Milan, 20132, Italy.
8
Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montreal, QC, H3A 0G1, Canada.
9
Department of Biochemistry and Goodman Cancer Centre, McGill University, Montreal, QC, H3A 1A3, Canada. nahum.sonenberg@mcgill.ca.

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.

PMID:
29941989
PMCID:
PMC6018502
DOI:
10.1038/s41467-018-04883-5
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center