Abstract
Clinical studies have found that ketamine has a rapid and lasting antidepressant effect, especially in the case of patients with major depressive disorder (MDD). The molecular mechanisms, however, remain unclear. In this study, we observe the effects of S-Ketamine on the expression of Rac1, neuronal morphology, and synaptic transmission function in the hippocampus of stressed rats. Chronic unpredictable mild stress (CUMS) was used to construct stressed rats. The rats were given a different regimen of ketamine (20 mg/kg, i.p.) and Rac1 inhibitor NSC23766 (50 µg, ICV) treatment. The depression-like behavior of rats was evaluated by sucrose preference test and open-field test. The protein expression of Rac1, GluA1, synapsin1, and PSD95 in the hippocampus was detected by Western blot. Pull-down analysis was used to examine the activity of Rac1. Golgi staining and electrophysiological study were used to observe the neuronal morphology and long-term potentiation (LTP). Our results showed that ketamine can up-regulate the expression and activity of Rac1; increase the spine density and the expression of synaptic-related proteins such as GluA1, Synapsin1, and PSD95 in the hippocampus of stressed rats; reduce the CUMS-induced LTP impairments; and consequently improve depression-like behavior. However, Rac1 inhibitor NSC23766 could have effectively reversed ketamine-mediated changes in the hippocampus of rats and counteracted its antidepressant effects. The specific mechanism of S-Ketamine's antidepressant effect may be related to the up-regulation of the expression and activity of Rac1 in the hippocampus of stressed rats, thus enhancing synaptic plasticity.
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Acknowledgements
The authors thank Jie Luo and Li Ren PhD. from the Department of Anesthesiology of the First Affiliated Hospital of Chongqing Medical University for their assistance in the study.
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This work was supported by the National Natural Science Foundation of China (Grant No. 81760257), the Science and Technology Department of Hubei Province (No. 2016CFB368) and Natural Science Foundation of Yongchuan District (Ycstc, 2020nb0205).
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Fuxia Yan and Zaiping Wang designed experiments. Fuxia Yan and Zaiping Wang: Designed the study and wrote the protocol. Xianlin Zhu and Fan Zhang established the animal model of depression and performed the behavioral tests, statistical analyses, and wrote the first draft of the manuscript. Yufeng You, Banglin Wu, and Rongyu Zhu performed the tissue preparation, RT-qPCR and western blotting analysis. Su Yuan and Dawei Liu performed the Golgi staining. Hongbai Wang performed the electrophysiological study. All authors contributed to the article and approved the submitted version.
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Zhu, X., Zhang, F., You, Y. et al. S-Ketamine Exerts Antidepressant Effects by Regulating Rac1 GTPase Mediated Synaptic Plasticity in the Hippocampus of Stressed Rats. Cell Mol Neurobiol 43, 299–314 (2023). https://doi.org/10.1007/s10571-021-01180-6
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DOI: https://doi.org/10.1007/s10571-021-01180-6