Abstract
Ketamine is a recreational drug that causes emotional and cognitive impairments, but its specific mechanisms of action are still unclear. Recent evidence suggests that Tau protein phosphorylation and targeted delivery to the postsynaptic area are closely related to its neurotoxicity, and our recent studies have shown that long-term ketamine administration causes excessive Tau protein phosphorylation. However, the regulatory mechanism of Tau protein phosphorylation induced by ketamine has not been clarified. In the present study, we administered a single ketamine injection and long-term (6 months) ketamine injections in C57BL/6 mice, to investigate the effects of different doses of ketamine on the expression levels of Tau protein and its phosphorylation, the expression levels and activities of the related protein phosphokinases GSK-3β and CDK5, and the expression levels and activities of the related protein phosphatases PP2A and PP2B in the mouse hippocampus. Our results showed that both single-dose and long-term ketamine administration induced excessive phosphorylation of the Tau protein at ser202/thr205 and ser396. A single ketamine administration caused an increase in the activity of GSK-3β (at high doses) and a decrease in the activity of PP2A. On the other hand, long-term ketamine administration resulted in an increase in the activities of GSK-3β (at high doses) and CDK5, and a decrease in the activity of PP2A. Our results indicate that GSK-3β, CDK5, and PP2A may be involved in ketamine-induced Tau protein phosphorylation.
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We are indebted to the participants for their dedication to this study.
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The present study was supported by grants from the National Natural Science Fund of China (81960341, 81971794, 81871852, 81671867), Liaoning Revitalization Talents Program (Grant No. XLYC1902059, XLYC1807137), Liaoning Provincial Key Research and Development Project (2020JH2/10300039), and Key Scientific Research Project of Gannan Medical University (ZD201828).
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XW and YNL conceived and designed the experiments. YNL, GHW, RTD, and XHR performed the experiments. CCJ, LL, and JY helped to analyze and interpret the data. YNL drafted the manuscript. XW, BML, GHZ, and YL provided critical revision. All authors reviewed and approved of the final manuscript.
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Li, Y., Wen, G., Ding, R. et al. Effects of Single-Dose and Long-Term Ketamine Administration on Tau Phosphorylation–Related Enzymes GSK-3β, CDK5, PP2A, and PP2B in the Mouse Hippocampus. J Mol Neurosci 70, 2068–2076 (2020). https://doi.org/10.1007/s12031-020-01613-9
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DOI: https://doi.org/10.1007/s12031-020-01613-9