The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder.
The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder.
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DOI：
10.1016/j.pnpbp.2011.05.010
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发表时间：
2011-08-15
影响因子：
5.6
通讯作者：
Karolewicz, Beata
中科院分区：
文献类型：
--
作者：
Jernigan, Courtney S.;Goswami, Dharmendra B.;Austin, Mark C.;Iyo, Abiye H.;Chandran, Agata;Stockmeier, Craig A.;Karolewicz, Beata
最近的研究表明，氯胺酮的快速抗抑郁反应是通过激活哺乳动物雷帕霉素靶点（mTOR）信号通路介导的，导致大鼠前额叶皮质（PFC）突触蛋白增加。我们的死后研究表明，重度抑郁症（MDD）患者PFC中显著的突触后蛋白缺失，包括n -甲基- d -天冬氨酸（NMDA）受体亚基（NR2A、NR2B）、代谢性谷氨酸受体亚型5 （mGluR5）和突触后密度蛋白95kda （PSD-95）。我们假设mtor依赖的翻译起始通路的缺陷导致了MDD受试者PFC中所见的分子病理，并且这些异常的快速逆转可能是抗抑郁活性的基础。大多数已知的翻译调控发生在起始水平。mTOR通过其下游组分：p70-kDa核糖体蛋白S6激酶（p70S6K）和真核起始因子4E和4B （eIF4E, eIF4B）调节翻译起始。在本研究中，我们使用Western blot检测了12名抑郁症患者和12名精神健康对照者PFC中mTOR及其核心下游信号靶点p70S6K、eIF4E、eIF4B的表达。eIF4E丝氨酸209位点磷酸化（p-eIF4E-Ser209）和eIF4B丝氨酸504位点磷酸化（p-eIF4B-Ser504）的水平也被检测。我们之前的死后分析中使用了来自两组受试者的邻近皮质组织样本。MDD患者的mTOR、p70S6K、eIF4B和p-eIF4B蛋白表达明显低于对照组。各组间eIF4E、p-eIF4E和actin水平均无差异。我们的研究结果显示MDD中mTOR依赖的翻译启动缺陷，特别是通过p70S6K/eIF4B途径，并表明突触蛋白的显着缺陷与MDD中mTOR信号失调之间存在潜在关联。
Recent studies demonstrate that rapid antidepressant response to ketamine is mediated by activation of the mammalian target of rapamycin (mTOR) signaling pathway, leading to increased synaptic proteins in the prefrontal cortex (PFC) of rats. Our postmortem studies indicate robust deficits in prominent postsynaptic proteins including N-methyl-D-aspartate (NMDA) receptor subunits (NR2A, NR2B), metabotropic glutamate receptor subtype 5 (mGluR5) and postsynaptic density protein 95 kDa (PSD-95) in the PFC in major depressive disorder (MDD). We hypothesize that deficits in the mTOR-dependent translation initiation pathway contribute to the molecular pathology seen in the PFC of MDD subjects, and that a rapid reversal of these abnormalities may underlie antidepressant activity. The majority of known translational regulation occurs at the level of initiation. mTOR regulates translation initiation via its downstream components: p70-kDa ribosomal protein S6 kinase (p70S6K), and eukaryotic initiation factors 4E and 4B (eIF4E, eIF4B). In this study, we examined the expression of mTOR and its core downstream signaling targets: p70S6K, eIF4E, eIF4B in the PFC of 12 depressed subjects and 12 psychiatrically healthy controls using Western blot. Levels of eIF4E phosphorylated at serine 209 (p-eIF4E-Ser209) and eIF4B phosphorylated at serine 504 (p-eIF4B-Ser504) were also examined. Adjacent cortical tissue samples from both cohorts of subjects were used in our previous postmortem analyses. There was a significant reduction in mTOR, p70S6K, eIF4B and p-eIF4B protein expression in MDD subjects relative to controls. No group differences were observed in eIF4E, p-eIF4E or actin levels. Our findings show deficits in mTOR-dependent translation initiation in MDD particularly via the p70S6K/eIF4B pathway, and indicate a potential association between marked deficits in synaptic proteins and dysregulation of mTOR signaling in MDD.
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DOI：
10.1126/science.1190287
发表时间：
2010-08-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Li N;Lee B;Liu RJ;Banasr M;Dwyer JM;Iwata M;Li XY;Aghajanian G;Duman RS
通讯作者：
Duman RS
影响因子：
11.4
作者：
Raught, B;Peiretti, F;Hershey, JWB
通讯作者：
Hershey, JWB
影响因子：
10.6
作者：
Berman, RM;Cappiello, A;Krystal, JH
通讯作者：
Krystal, JH
影响因子：
15.9
作者：
Hoeffer, Charles A.;Klann, Eric
通讯作者：
Klann, Eric
影响因子：
3.4
作者：
Dagestad, Grethe;Kuipers, Sjoukje D.;Bramham, Clive R.
通讯作者：
Bramham, Clive R.