The MAPK/ERK (Mitogen Activated Protein Kinases/Extracellular signal-Regulated Kinases) pathway is a cardinal regulator of synaptic plasticity, learning and memory in the hippocampus. One of major endpoints of this signaling cascade is the 5' mRNA cap-binding protein eIF4E (eukaryotic Initiation Factor 4E), which is phosphorylated on Ser 209 by MNK (MAPK-interacting protein kinases) and controls mRNA translation. The precise role of phospho-eIF4E in the brain is yet to be determined. Herein, we demonstrate that ablation of eIF4E phosphorylation in male mice (4Eki mice) does not impair long-term spatial or contextual fear memory, or the late phase of long-term potentiation (L-LTP). Using unbiased translational profiling in mouse brain, we show that phospho-eIF4E differentially regulates the translation of a subset of mRNAs linked to inflammation, the extracellular matrix (ECM), pituitary hormones and the serotonin pathway. Consequently, 4Eki male mice display exaggerated inflammatory responses and reduced levels of serotonin, concomitant with depression and anxiety-like behaviors. Remarkably, eIF4E phosphorylation is required for the chronic antidepressant action of the selective serotonin reuptake inhibitor (SSRI) fluoxetine. Finally, we propose a novel phospho-eIF4E-dependent translational control mechanism in the brain, via the GAIT complex (Gamma interferon Activated Inhibitor of Translation). In summary, our work proposes a novel translational control mechanism involved in the regulation of inflammation and depression, which could be exploited to design novel therapeutics.SIGNIFICANCE STATEMENTWe demonstrate that downstream of the Mitogen Activated Protein Kinase (MAPK) pathway, eukaryotic Initiation Factor 4E (eIF4E) Ser209 phosphorylation is not required for classical forms of hippocampal long-term potentiation and memory. We reveal a novel role for eIF4E phosphorylation in inflammatory responses and depression-like behaviors. eIF4E phosphorylation is required for the chronic action of antidepressants such as fluoxetine in mice. These phenotypes are accompanied by selective translation of extracellular matrix, pituitary hormones and serotonin pathway genes, in eIF4E phospho-mutant mice. We also describe a previously unidentified translational control mechanism in the brain, whereby eIF4E phosphorylation is required for inhibiting the translation of Gamma interferon Activated Inhibitor of Translation (GAIT) element-containing mRNAs. These findings can be used to design novel therapeutics for depression.