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Hypermethylation of Hippocampal Synaptic Plasticity-Related genes is Involved in Neonatal Sevoflurane Exposure-Induced Cognitive Impairments in Rats

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Abstract

General anesthetics given to immature rodents cause delayed neurobehavioral abnormalities via incompletely understood mechanisms. DNA methylation, one of the epigenetic modifications, is essential for the modulation of hippocampal synaptic plasticity through regulating the related genes. Therefore, we investigated whether abnormalities in the hippocampal DNA methylation of synaptic plasticity-related genes are involved in neonatal sevoflurane exposure-induced cognitive impairments in rats. Male Sprague–Dawley rats were exposed to 3 % sevoflurane or 30 % oxygen/air for 2 h daily from postnatal day 7 (P7) to P9 and were treated with DNA methyltransferases (DNMTs) inhibitor 5-aza-2-deoxycytidine (5-AZA) or vehicle 1 h before the first sevoflurane exposure on P7. The rats were euthanized 1, 6, 24 h, and 30 days after the last sevoflurane exposure, and the brain tissues were harvested for biochemical analysis. Cognitive functions were evaluated by the open field, fear conditioning, and Morris water maze (MWM) tests on P39, P41–43, and P50–57, respectively. In the present study, repeated neonatal sevoflurane exposure resulted in hippocampus-dependent cognitive impairments as assessed by fear conditioning and MWM tests. The cognitive impairments were associated with the increased DNMTs and hypermethylation of brain-derived neurotrophic factor (BDNF) and Reelin genes, and subsequent down-regulation of BDNF and Reelin genes, which finally led to the decrease of dendritic spines in the hippocampal pyramidal neurons in adolescent rats. Notably, pretreatment with 5-AZA reversed these sevoflurane-induced abnormalities. In conclusion, our results suggest that hypermethylation of hippocampal BDNF and Reelin is involved in neonatal sevoflurane exposure-induced cognitive impairments.

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Acknowledgments

This work was supported by the grants from the National Natural Science Foundation of China (Nos. 81271216 and 81300946).

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Authors and Affiliations

  1. Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China

    Ling-sha Ju, Min Jia, Xiao-ru Sun, Hui Zhang, Mu-huo Ji & Jian-jun Yang

  2. Department of Anesthesiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Jie Sun & Zhong-yun Wang

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  1. Ling-sha Ju
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  2. Min Jia
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Correspondence to Zhong-yun Wang.

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Ju, Ls., Jia, M., Sun, J. et al. Hypermethylation of Hippocampal Synaptic Plasticity-Related genes is Involved in Neonatal Sevoflurane Exposure-Induced Cognitive Impairments in Rats. Neurotox Res 29, 243–255 (2016). https://doi.org/10.1007/s12640-015-9585-1

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