Fluoxetine regulates mTOR signalling in a region-dependent manner in depression-like mice.
Fluoxetine regulates mTOR signalling in a region-dependent manner in depression-like mice.
复制标题
氟西汀在抑郁样小鼠中以区域依赖性方式调节 mTOR 信号传导。
DOI：
10.1038/srep16024
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发表时间：
2015-11-02
影响因子：
4.6
通讯作者：
Yi LT
中科院分区：
文献类型：
--
作者：
Liu XL;Luo L;Mu RH;Liu BB;Geng D;Liu Q;Yi LT
先前的研究表明，尽管氟西汀急性给药不影响大脑中mTOR的磷酸化，但雷帕霉素（mTOR）信号通路的哺乳动物靶点在氯胺酮诱导的快速抗抑郁作用中起重要作用。然而，长期氟西汀治疗对mTOR调节的影响迄今尚未得到评估。在本研究中，我们研究了氟西汀（一种常用的抗抑郁药物）是否会改变大脑不同区域（包括额叶皮质、海马、杏仁核和下丘脑）的mTOR信号。我们还研究了氟西汀是否通过激活mTOR信号通路及其下游调节因子p70S6K和4E-BP-1来提高这些区域的突触蛋白水平。结果表明，慢性氟西汀治疗减轻了慢性、不可预测的轻度应激（CUMS）诱导的小鼠海马和杏仁核mTOR磷酸化减少，但在额叶皮层和下丘脑没有。此外，氟西汀可逆转cums降低的PSD-95和突触素I水平，而雷帕霉素仅能在海马区阻断这些作用。总之，我们的研究结果表明，氟西汀慢性治疗可以通过激活mTOR信号通路以区域依赖的方式诱导突触蛋白表达，主要在海马中。
Previous studies have demonstrated that the mammalian target of rapamycin (mTOR) signaling pathway has an important role in ketamine-induced, rapid antidepressant effects despite the acute administration of fluoxetine not affecting mTOR phosphorylation in the brain. However, the effects of long-term fluoxetine treatment on mTOR modulation have not been assessed to date. In the present study, we examined whether fluoxetine, a type of commonly used antidepressant agent, alters mTOR signaling following chronic administration in different brain regions, including the frontal cortex, hippocampus, amygdala and hypothalamus. We also investigated whether fluoxetine enhanced synaptic protein levels in these regions via the activation of the mTOR signaling pathway and its downstream regulators, p70S6K and 4E-BP-1. The results indicated that chronic fluoxetine treatment attenuated the chronic, unpredictable, mild stress (CUMS)-induced mTOR phosphorylation reduction in the hippocampus and amygdala of mice but not in the frontal cortex or the hypothalamus. Moreover, the CUMS-decreased PSD-95 and synapsin I levels were reversed by fluoxetine, and these effects were blocked by rapamycin only in the hippocampus. In conclusion, our findings suggest that chronic treatment with fluoxetine can induce synaptic protein expression by activating the mTOR signaling pathway in a region-dependent manner and mainly in the hippocampus.