Neonatal Sevoflurane Exposure Impairs Learning and Memory by the Hypermethylation of Hippocampal Synaptic Genes
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Neonatal Sevoflurane Exposure Impairs Learning and Memory by the Hypermethylation of Hippocampal Synaptic Genes Xin-Yu Fan 1 & Guang Shi 2
&
Ping Zhao 1
Received: 28 August 2020 / Accepted: 4 October 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Sevoflurane anesthesia is widely used in pediatric patients. Clinical studies report memory impairment in those exposed to general anesthesia early in life. DNA methylation is essential for the modulation of synaptic plasticity through regulating the transcription of synaptic genes. Therefore, we tested whether neonatal sevoflurane exposure affects learning and memory underlying the hippocampal DNA methylation of synaptic genes. Male Sprague-Dawley rats were exposed to 3% sevoflurane or air for 2 h daily from postnatal day 7 (P7) to P9. 5-aza-2-deoxycytidine (5-AZA), an inhibitor of DNA methyltransferases (DNMTs), was intraperitoneally injected 30 min before sevoflurane or air exposure on P7–9. The rats were euthanized 6, 12, 24 h, and 28 days after the last sevoflurane exposure, followed by the determination of global and gene-specific DNA methylation. The expression of synaptic proteins and synaptic density and the transcription of Dnmts and ten eleven translocations (Tets) in the hippocampus were measured. The ability of learning and memory was assessed using Morris water maze, novel object recognition, and intruder tests. Repeated neonatal sevoflurane exposure impaired cognitive, social, and spatial memory. The memory impairment was associated with the increased Dnmt1, Dnmt3a, and 5-methylcytosine level and the decreased Tet1 and 5-hydromethylcytosine level. Sevoflurane subsequently induced hypermethylation of Shank2, Psd95, Syn1, and Syp gene and down-regulated the expression of synaptic proteins, which finally led to the decrease of synaptic density in a time-dependent manner. Notably, 5-AZA pretreatment ameliorated learning and memory in sevoflurane-treated rats. In conclusion, neonatal exposure to sevoflurane can impair learning and memory through DNA methylation of synaptic genes. Keywords DNA methylation . Sevoflurane . Spatial memory . Synaptic proteins . 5-AZA
Introduction General anesthesia can cause memory impairment, resulting in loss of consciousness and memory defects in the brain of newborns [1, 2]. Sevoflurane is one of the most commonly used volatile anesthetics in infants. Many basic studies have revealed that sevoflurane exposure to the developing brain can cause long-term neurocognitive impairment and learning disability in the adulthood [3, 4]. In addition, clinical reports have Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-020-02161-4) contains supplementary material, which is available to authorized users. * Ping Zhao [email protected] 1
Department of Anesthesiology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Shenyang 110004, China
2
Department of Neurology, Liaoning Provincial People’s Hospital, Shenyang, China
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