Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom.
Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom.
J Neurosci. 2018 Feb 21;38(8):2118-2133. doi: 10.1523/JNEUROSCI.2673-17.2018. Epub 2018 Jan 24.
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 ( 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, 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. 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.
MAPK/ERK（丝裂原活化蛋白激酶/细胞外信号调节激酶）途径是调节海马体突触可塑性、学习和记忆的主要调控因子。该信号级联反应的主要终点之一是 5' mRNA 帽结合蛋白 eIF4E（真核起始因子 4E），它可被 MNK（MAPK 相互作用蛋白激酶）磷酸化 Ser209，从而控制 mRNA 翻译。磷酸化 eIF4E 在大脑中的精确作用仍有待确定。在此，我们证明在雄性小鼠（eIF4E 磷酸化敲除小鼠）中敲除 eIF4E 磷酸化不会损害长时程空间或情景恐惧记忆，或 LTP 的晚期阶段。通过在小鼠大脑中进行无偏翻译谱分析，我们表明磷酸化 eIF4E 差异调节与炎症、细胞外基质、垂体激素和 5-羟色胺途径相关的一组 mRNA 的翻译。因此，eIF4E 磷酸化敲除小鼠表现出炎症反应过度和 5-羟色胺水平降低，同时伴有抑郁和焦虑样行为。值得注意的是，选择性 5-羟色胺再摄取抑制剂氟西汀的慢性抗抑郁作用需要 eIF4E 磷酸化。最后，我们提出了一种新的脑内磷酸化 eIF4E 依赖性翻译控制机制，通过 GAIT 复合物（γ干扰素激活的翻译抑制剂）。总之，我们的工作提出了一种新的翻译控制机制，涉及炎症和抑郁的调节，这可能被用于设计新的治疗方法。我们证明，在 MAPK（丝裂原活化蛋白激酶）途径下游，真核起始因子 4E（eIF4E）Ser209 磷酸化对于经典形式的海马体 LTP 和记忆并不必需。我们揭示了 eIF4E 磷酸化在炎症反应和抑郁样行为中的新作用。eIF4E 磷酸化是氟西汀等抗抑郁药在小鼠中发挥慢性作用所必需的。这些表型伴随着细胞外基质、垂体激素和 5-羟色胺途径基因的选择性翻译，在 eIF4E 磷酸化突变小鼠中。我们还描述了一种在脑中以前未被识别的翻译控制机制，即 eIF4E 磷酸化对于抑制 γ干扰素激活的翻译抑制剂元件包含的 mRNAs 的翻译是必需的。这些发现可用于设计治疗抑郁症的新疗法。
