Orphan receptor GPR158 controls stress-induced depression.
Orphan receptor GPR158 controls stress-induced depression.
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DOI：
10.7554/elife.33273
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发表时间：
2018-02-08
期刊：
影响因子：
7.7
通讯作者：
Martemyanov KA
中科院分区：
文献类型：
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作者：
Sutton LP;Orlandi C;Song C;Oh WC;Muntean BS;Xie K;Filippini A;Xie X;Satterfield R;Yaeger JDW;Renner KJ;Young SM Jr;Xu B;Kwon H;Martemyanov KA
压力可以成为采取果断行动和适应新环境的动力；然而，暴露在长期压力下会导致抑郁和焦虑的发展。然而，压力响应行为背后的分子机制还没有完全被理解。在这里，我们确定孤儿受体GPR158是一种新的调节因子，它工作在前额叶皮质(PFC)，将慢性应激与抑郁联系起来。GPR158在患有严重抑郁障碍的受试者的PFC中高度上调。小鼠暴露在慢性应激中也以糖皮质激素依赖的方式增加了PFC中GPR158蛋白的水平。病毒过表达GPR158在PFC诱导的抑郁样行为中的作用相比之下，GPR158消融导致了显著的抗抑郁药样表型和应激弹性。我们发现GPR158通过调节突触强度改变AMPA受体活性而发挥作用。综上所述，我们的发现确定了情绪调节的新参与者，并引入了管理抑郁的药理学目标。
Stress can be a motivational force for decisive action and adapting to novel environment; whereas, exposure to chronic stress contributes to the development of depression and anxiety. However, the molecular mechanisms underlying stress-responsive behaviors are not fully understood. Here, we identified the orphan receptor GPR158 as a novel regulator operating in the prefrontal cortex (PFC) that links chronic stress to depression. GPR158 is highly upregulated in the PFC of human subjects with major depressive disorder. Exposure of mice to chronic stress also increased GPR158 protein levels in the PFC in a glucocorticoid-dependent manner. Viral overexpression of GPR158 in the PFC induced depressive-like behaviors. In contrast GPR158 ablation, led to a prominent antidepressant-like phenotype and stress resiliency. We found that GPR158 exerts its effects via modulating synaptic strength altering AMPA receptor activity. Taken together, our findings identify a new player in mood regulation and introduce a pharmacological target for managing depression.