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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Anxiety / chemically induced
  • Anxiety / genetics
  • Anxiety / pathology*
  • Behavior, Animal / physiology
  • Benzofurans / pharmacology
  • Citalopram / pharmacology
  • Depression / chemically induced
  • Depression / genetics
  • Depression / pathology*
  • Depressive Disorder, Major / pathology
  • Eukaryotic Initiation Factor-4E / metabolism*
  • Female
  • Fluoxetine / pharmacology
  • Inflammation / pathology
  • Ketamine / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-KappaB Inhibitor alpha / metabolism
  • Phosphorylation
  • Protein Biosynthesis / physiology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics*
  • Serotonin and Noradrenaline Reuptake Inhibitors / pharmacology
  • Synaptic Transmission / physiology
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Antidepressive Agents
  • Benzofurans
  • Eukaryotic Initiation Factor-4E
  • Serotonin and Noradrenaline Reuptake Inhibitors
  • Tumor Necrosis Factor-alpha
  • eIF4E protein, mouse
  • Fluoxetine
  • Citalopram
  • cercosporamide
  • NF-KappaB Inhibitor alpha
  • Ketamine
  • Mknk1 protein, mouse
  • Mknk2 protein, mouse
  • Protein-Serine-Threonine Kinases