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Neurotoxicity Research

Erschienen in:

01.02.2016 | Original Article

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

verfasst von: Ling-sha Ju, Min Jia, Jie Sun, Xiao-ru Sun, Hui Zhang, Mu-huo Ji, Jian-jun Yang, Zhong-yun Wang

Erschienen in: Neurotoxicity Research | Ausgabe 2/2016

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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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Titel: Hypermethylation of Hippocampal Synaptic Plasticity-Related genes is Involved in Neonatal Sevoflurane Exposure-Induced Cognitive Impairments in Rats
verfasst von: Ling-sha Ju
Min Jia
Jie Sun
Xiao-ru Sun
Hui Zhang
Mu-huo Ji
Jian-jun Yang
Zhong-yun Wang
Publikationsdatum: 01.02.2016
Verlag: Springer US
Erschienen in: Neurotoxicity Research / Ausgabe 2/2016
Print ISSN: 1029-8428
Elektronische ISSN: 1476-3524
DOI: https://doi.org/10.1007/s12640-015-9585-1

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