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

被引:58
作者
Amorim, Ines S. [1 ,2 ]
Kedia, Sonal [1 ,2 ]
Kouloulia, Stella [1 ,2 ]
Simbriger, Konstanze [1 ,2 ]
Gantois, Ilse [3 ,4 ]
Jafarnejad, Seyed Mehdi [3 ,4 ]
Li, Yupeng [1 ,2 ]
Kampaite, Agniete [1 ,2 ]
Pooters, Tine [1 ]
Romano, Nicola [1 ]
Gkogkas, Christos G. [1 ,2 ,5 ]
机构
[1] Univ Edinburgh, Ctr Discovery Brain Sci, Edinburgh EH8 9XD, Midlothian, Scotland
[2] Univ Edinburgh, Patrick Wild Ctr, Edinburgh EH8 9XD, Midlothian, Scotland
[3] McGill Univ, Goodman Canc Res Ctr, Montreal, PQ H3A 1A3, Canada
[4] McGill Univ, Biochem Dept, Montreal, PQ H3A 1A3, Canada
[5] Univ Edinburgh, Simons Initiat Developing Brain, Edinburgh EH8 9XD, Midlothian, Scotland
基金
英国惠康基金;
关键词
depression; eIF4E; inflammation; phospho-eIF4E; translation; INITIATION-FACTOR; 4E; TERM SYNAPTIC PLASTICITY; FRAGILE-X-SYNDROME; PROTEIN-SYNTHESIS; CHRONIC FLUOXETINE; DEPENDENT MANNER; KINASE CASCADE; ANIMAL-MODELS; MAPK CASCADE; WEB SERVER;
D O I
10.1523/JNEUROSCI.2673-17.2018
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:2118 / 2133
页数:16
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