Department of Psychiatry and Behavioral Science, Seoul National University College of Medicine, Seoul, Republic of Korea.
Int J Neuropsychopharmacol. 2010 Oct;13(9):1233-46. doi: 10.1017/S1461145709991192. Epub 2010 Jan 11.
Systemic injections of MK-801, a selective NMDAR antagonist, into neonatal rats induces long-term neurochemical and behavioural changes. It has been suggested that these changes form the neurodevelopmental basis for schizophrenia-like behaviour in rats. In this study, 7-d-old rats were treated with MK-801, and their frontal cortices were examined to investigate the effects on p70S6K-S6 signal pathway and on protein translation, which play crucial roles in the neurodevelopmental process. MK-801, in doses of 0.5 and 1.0 mg/kg, induced a decrease in phosphorylation of p70S6K and its substrates, S6 and eIF4B, in the first 8 h, and no change at 24 and 48 h. These effects were more prominent after two injections of MK-801 than one. Decreased S6 phosphorylation by MK-801 was evident in the prefrontal, cingulate, and insular cortex. In two representative upstream p70S6K-S6 pathways related to ERK1/2 and Akt, changes in ERK1/2-p90RSK phosphorylation were accompanied by changes of p70S6K-S6. Although two MK-801 injections induced a dose-dependent decrease in phosphorylation of Akt and mTOR at 4 and 8 h, a single injection did not produce a significant effect. Protein synthesis rate, measured by [3H]leucine incorporation in frontal cortical tissue, was reduced until 24 h after two MK-801 (1.0 mg/kg) injections. In summary, this study found that neonatal MK-801 treatment induced dysregulation in the p70S6K-S6/eIF4B pathway and protein translation in the frontal cortex of the developing rat brain, which may suggest an important role of protein translation machinery in the MK-801 neurodevelopmental animal model of schizophrenia.
MK-801 是一种选择性 NMDAR 拮抗剂，对新生大鼠进行全身注射会导致长期的神经化学和行为改变。有人认为，这些变化构成了大鼠类似精神分裂症行为的神经发育基础。在这项研究中，对 7 天大的大鼠进行了 MK-801 治疗，并检查了它们的前额皮质，以研究其对 p70S6K-S6 信号通路和蛋白质翻译的影响，这在神经发育过程中起着至关重要的作用。MK-801 的剂量为 0.5 和 1.0mg/kg，在最初的 8 小时内会导致 p70S6K 和其底物 S6 和 eIF4B 的磷酸化减少，而在 24 和 48 小时时没有变化。MK-801 进行两次注射的效果比一次注射更为显著。MK-801 导致 S6 磷酸化减少的情况在额皮质、扣带回和脑岛皮质中更为明显。在两个与 ERK1/2 和 Akt 相关的代表性 p70S6K-S6 通路中，ERK1/2-p90RSK 磷酸化的变化伴随着 p70S6K-S6 的变化。虽然两次 MK-801 注射会导致 Akt 和 mTOR 的磷酸化在 4 和 8 小时时呈剂量依赖性下降，但单次注射不会产生显著效果。通过前额皮质组织中 [3H]亮氨酸掺入来测量蛋白质合成率，直到两次 MK-801（1.0mg/kg）注射后 24 小时才会降低。总之，这项研究发现，新生大鼠的 MK-801 处理会导致前额皮质发育中的 p70S6K-S6/eIF4B 通路和蛋白质翻译失调，这可能表明蛋白质翻译机制在精神分裂症的 MK-801 神经发育动物模型中起着重要作用。
