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Inhibition of RhoA Activity Does Not Rescue Synaptic Development Abnormalities and Long-Term Cognitive Impairment After Sevoflurane Exposure

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Abstract

General anesthetics interfere with dendritic development and synaptogenesis, resulting in cognitive impairment in the developing animals. RhoA signal pathway plays important roles in dendritic development by regulating cytoskeleton protein such as tubulin and actin. However, it’s not clear whether RhoA pathway is involved in inhaled general anesthetics sevoflurane-induced synaptic development abnormalities and long-term cognitive dysfunction. Rats at postnatal day 7 (PND7) were injected intraperitoneally with RhoA pathway inhibitor Y27632 or saline 20 min before exposed to 2.8% sevoflurane for 4 h. The apoptosis-related proteins and RhoA/CRMP2 pathway proteins in the hippocampus were measured 6 h after sevoflurane exposure. Cognitive functions were evaluated by the open field test on PND25 rats and contextual fear conditioning test on PND32-33 rats. The dendritic morphology and density of dendritic spines in the pyramidal neurons of hippocampus were determined by Golgi staining and the synaptic plasticity-related proteins were also measured on PND33 rats. Long term potentiation (LTP) from hippocampal slices was recorded on PND34-37 rats. Sevoflurane induced caspase-3 activation, decreased the ratio of Bcl-2/Bax and increased TUNEL-positive neurons in hippocampus of PND7 rats, which were attenuated by inhibition of RhoA. However, sevoflurane had no significant effects on activity of RhoA/CRMP2 pathway. Sevoflurane disturbed dendritic morphogenesis, reduced the number of dendritic spines, decreased proteins expression of PSD-95, drebrin and synaptophysin, inhibited LTP in hippocampal slices and impaired memory ability in the adolescent rats, while inhibition of RhoA activity did not rescue the changes above induced by sevoflurane. RhoA signal pathway did not participate in sevoflurane-induced dendritic and synaptic development abnormalities and cognitive dysfunction in developing rats.

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Abbreviations

CRMP2:

Collapsin response mediator protein 2

PND7:

Postnatal day 7

LTP:

Long term potentiation

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81371259); the Natural Science Foundation of Guangdong Province, China (Nos. 2016A030313251; 2018A0303130272); the Science and Technology Planning Project of Guangzhou, China (No. 201707010207) and the fundamental research funds for the central universities (No. 17ykjc26).

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  1. Zhaoxia Liao and Junhua Li have contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 107 Yanjiang West Road, Guangzhou, 510120, China

    Zhaoxia Liao, Junhua Li, Liping Miao, Zeqi Huang, Wujian Huang, Yafang Liu & Yujuan Li

  2. Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China

    Zhaoxia Liao, Junhua Li, Liping Miao, Zeqi Huang, Wujian Huang, Yafang Liu & Yujuan Li

  3. Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China

    Yujuan Li

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Contributions

ZL and JL: Investigation, Methodology, Writing, Original draft preparation. HL and LM: Conceptualization, Data curation. ZH, WH and YL: Visualization, Software, Supervision. YL: Designing, Writing-Reviewing and Editing.

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Liao, Z., Li, J., Miao, L. et al. Inhibition of RhoA Activity Does Not Rescue Synaptic Development Abnormalities and Long-Term Cognitive Impairment After Sevoflurane Exposure. Neurochem Res 46, 468–481 (2021). https://doi.org/10.1007/s11064-020-03180-2

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