1Departments of Cell Biology, Physiology and Neuroscience, and Psychiatry, Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, New York University Langone School of Medicine, New York, NY 10016, USA.
Sci Signal. 2014 Jan 14;7(308):ra4. doi: 10.1126/scisignal.2004331.
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. 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.
虽然抗精神病药物可以在数小时内减少精神病症状，但要达到完全疗效需要数周时间，这表明神经元功能可能会发生快速的短期变化，这些变化会被巩固为持久的变化。我们发现，抗精神病药物氟哌啶醇是一种多巴胺受体 2（D₂R）拮抗剂，它能刺激激酶 Akt 激活雷帕霉素靶蛋白复合物 1（mTORC1）介导的 mRNA 翻译途径。在原代纹状体 D₂R 阳性神经元中，氟哌啶醇介导的 mTORC1 激活导致核糖体蛋白 S6（S6）和真核翻译起始因子 4E 结合蛋白（4E-BP）磷酸化增加。蛋白质组学质谱分析显示，在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明显变化，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神经元形态复杂性的增加相吻合，而 mTORC1 的下游效应物抑制剂则减弱了这种增加，这表明 mTORC1 依赖性翻译增强了神经元对氟哌啶醇的复杂性。在体内，我们观察到氟哌啶醇注射小鼠皮质神经元的形态迅速变化，同时细胞骨架蛋白的丰度增加。这些结果为抗精神病药物的急性和长期作用提供了一种机制。
