Antipsychotics activate mTORC1-dependent translation to enhance neuronal morphological complexity.
Antipsychotics activate mTORC1-dependent translation to enhance neuronal morphological complexity.
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DOI：
10.1126/scisignal.2004331
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发表时间：
2014-01-14
影响因子：
7.3
通讯作者：
Chao MV
中科院分区：
文献类型：
--
作者：
Bowling H;Zhang G;Bhattacharya A;Pérez-Cuesta LM;Deinhardt K;Hoeffer CA;Neubert TA;Gan WB;Klann E;Chao MV
虽然抗精神病药物可以在几小时内减少精神病行为，但几周内无法达到完全疗效，这意味着神经元功能可能会发生快速，短期的变化，这些变化会巩固为长期的变化。在这里，我们发现抗精神病药物氟哌啶醇（一种多巴胺受体2型（D2 R）拮抗剂）刺激激酶Akt，以激活由哺乳动物雷帕霉素靶点复合物1（mTORC 1）介导的mRNA翻译途径。在原代纹状体D2 R阳性神经元中，氟哌啶醇介导的mTORC 1激活导致核糖体蛋白S6（S6）和真核翻译起始因子4 E结合蛋白（4 E-BP）磷酸化增加。蛋白质组学质谱分析显示，培养的纹状体神经元急性暴露于氟哌啶醇后，蛋白质合成模式发生了显着变化，包括细胞骨架蛋白和与翻译机制相关的蛋白质丰度增加。这些蛋白质组学变化与mTORC 1下游效应物抑制减少的神经元形态复杂性增加相一致，表明mTORC 1依赖性翻译增强了对氟哌啶醇反应的神经元复杂性。在体内，我们观察到快速的形态学变化，伴随着氟哌啶醇注射小鼠皮质神经元中细胞骨架蛋白丰度的增加。这些结果表明，抗精神病药物的急性和长期作用的机制。
Although antipsychotic drugs can reduce psychotic behavior within a few hours, full efficacy is not achieved for several weeks, implying that there may be rapid, short-term changes in neuronal function, which are consolidated into long-lasting changes. Here, we showed that the antipsychotic drug haloperidol, a dopamine receptor type 2 (D2R) antagonist, stimulated the kinase Akt to activate the mRNA translation pathway mediated by the mammalian target of rapamycin complex 1 (mTORC1). In primary striatal D2R-positive neurons, haloperidol-mediated activation of mTORC1 resulted in increased phosphorylation of ribosomal protein S6 (S6) and eukaryotic translation initiation factor 4E-binding protein (4E-BP). Proteomic mass spectrometry revealed marked changes in the pattern of protein synthesis after acute exposure of cultured striatal neurons to haloperidol, including increased abundance of cytoskeletal proteins and proteins associated with translation machinery. These proteomic changes coincided with increased morphological complexity of neurons that was diminished by inhibition of downstream effectors of mTORC1, suggesting that mTORC1-dependent translation enhances neuronal complexity in response to haloperidol. In vivo, we observed rapid morphological changes with a concomitant increase in the abundance of cytoskeletal proteins in cortical neurons of haloperidol-injected mice. These results suggest a mechanism for both the acute and long-term actions of antipsychotics.
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影响因子：
17.7
作者：
Kapur, S;Arenovich, T;Jones, B
通讯作者：
Jones, B
影响因子：
3.3
作者：
BOUTHENET, ML;MARTRES, MP;SCHWARTZ, JC
通讯作者：
SCHWARTZ, JC
影响因子：
2.8
作者：
Bálint, E;Kitka, T;Csillag, A
通讯作者：
Csillag, A
影响因子：
30.8
作者：
Emamian, ES;Hall, D;Gogos, JA
通讯作者：
Gogos, JA
影响因子：
14.5
作者：
Kreczmanski, Pawel;Heinsen, Helmut;Schmitz, Christoph
通讯作者：
Schmitz, Christoph