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 language||English (US)|
|State||Published - Dec 1 2018|
Bibliographical noteFunding Information:
We thank David E. Szymkowski (Xencor, Inc., Monrovia, CA) for the generous donation of XPro1595; Jeremy Graff (Eli Lilly, Indianapolis, IN) for the generous donation of cercosporamide, and Annie Sylvestre, Annik Lafrance, Isabelle Harvey, Isabel Laplante, Luca Posa, Ada Posner, Grace Ling, Joshua Byer, Doreen Marks and Hansen Tsui for technical assistance. We thank Prof. Joseph Rochford for his help in data analysis. A.A.-V. was recipient of FRQS (Fond Recherche Québec-Santé) and CIHR (Canadian Institutes for Health Research) postdoctoral fellowships. D.D.G. was a recipient of FQRNT (Fonds de Recherche du Québec – Nature et technologies) postdoctoral fellowship. N.N. was supported by the Quebec Network on Suicide, Mood Disorders and Related Disorders. J.-C.L. is the recipient of the Canada Research Chair in Cellular and Molecular Neurophysiology. This work was supported by a CIHR Foundation grant to N.S. (FND-148423), a CIHR operating grant to J.-C.L. (MOP-125985), and a Fonds de la Recherche du Québec - Santé (FRQS) Group grant (Groupe de Recherche sur le Système Nerveux Central [GRSNC]) to J.-C.L.
© 2018 The Author(s).