Loss of eIF4E Phosphorylation Engenders Depression-like Behaviors via Selective mRNA Translation

Abstract

The MAPK/ERK (mitogen-activated protein kinases/extracellular signal-regulated kinase) 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 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, 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 fluoxetine. Finally, we propose a novel phospho-eIF4E-dependent translational control mechanism in the brain, via the GAIT complex (gamma IFN 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 STATEMENT We demonstrate that downstream of the MAPK (mitogen-activated protein kinase) pathway, eukaryotic Initiation Factor 4E (eIF4E) Ser209 phosphorylation is not required for classical forms of hippocampal LTP 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 IFN activated inhibitor of translation element-containing mRNAs. These findings can be used to design novel therapeutics for depression.

Nociceptor translational profiling reveals the RagA-mTORC1 network as a critical generator of neuropathic pain

“…S10A-B). This parallels previous findings that Mnk1/2 controls the translation of a specific subset of mRNAs (19,26). Paclitaxel-treated mice given eFT508 after full development of CIPN showed a dose-related reversal of mechanical and thermal hypersensitivity (Fig.…”

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

“…While the current study was being considered for publication, a different research group reported depression-like behaviors and increased inflammatory responses in the Eif4e ki/ki mice 66 . Behavioral phenotypes in our Eif4e ki/ki mouse testing are consistent with those reported by reference 66 .…”

“…While the current study was being considered for publication, a different research group reported depression-like behaviors and increased inflammatory responses in the Eif4e ki/ki mice 66 . Behavioral phenotypes in our Eif4e ki/ki mouse testing are consistent with those reported by reference 66 . In addition, our study demonstrated the involvement of MNK1 and MNK2 as the upstream kinases of eIF4E, and demonstrate the involvement of TNFα as a mediator of serotonergic neurotransmission impairment in the PFC and the DR, as a consequence of decreased eIF4E phosphorylation and attenuated translation of the mRNA encoding IκBα.…”

eIF4E-Dependent Translational Control: A Central Mechanism for Regulation of Pain Plasticity

“…In the brain, eIF4E phosphorylation controls the translation of mRNAs involved in inflammatory responses such as IκBα, a repressor of the transcription factor NF-κB that regulates the expression of the cytokine tumor necrosis factor (TNFα) ( Aguilar-Valles et al, 2018 ). Genome-wide translational profiling of the brain from eIF4E S209A mice revealed that eIF4E phosphorylation controls translation of mRNAs involved in inflammation (IL-2 and TNFα), organization of the extracellular matrix ( Prg2 , Mmp9 , Adamts16 , Acan ), and the serotonin pathway ( Slc6a4 ) ( Amorim et al, 2018 ).…”