2. Academic Validation
  3. A decrease in NR2B expression mediated by DNA hypermethylation induces perioperative neurocognitive disorder in aged mice

A decrease in NR2B expression mediated by DNA hypermethylation induces perioperative neurocognitive disorder in aged mice

  • CNS Neurosci Ther. 2023 Jan 24. doi: 10.1111/cns.14097.
Feifei Xu 1,  Peilin Cong 2,  Bingqian Zhang 3,  Hailong Dong 1,  Wenqiang Zuo 1,  Tingmei Wu 2,  Li Tian 2,  Lize Xiong 1 2
Affiliations

Affiliations

  • 1 Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
  • 2 Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, Translational Research Institute of Brain and Brain-Like Intelligence Affiliated to Tongji University School of Medicine, Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai, China.
  • 3 Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
PMID: 36694341 DOI: 10.1111/cns.14097
Abstract

Aims: This study was designed to investigate the role of NR2B and the contribution of DNA methylation to NR2B expression in the pathogenesis of PND.

Methods: Eighteen-month-old C57BL/6J mice were subjected to experimental laparotomy under 1.4% isoflurane anesthesia. Hippocampus-dependent learning and memory were evaluated by using the Barnes maze and contextual fear conditioning tests. The protein and mRNA expression levels of NR2B were evaluated by western blotting and qRT-PCR respectively, and the methylation of the NR2B gene was examined by using targeted bisulfite sequencing. Long-term synaptic plasticity (LTP) was measured by electrophysiology.

Results: Mice that underwent laparotomy exhibited hippocampus-dependent cognitive deficits accompanied by decreased NR2B expressions and LTP deficiency. The overexpression of NR2B in the dorsal hippocampus could improve learning and memory in mice subjected to laparotomy. In particular, the decreased NR2B expressions induced by laparotomy was attributed to the NR2B gene hypermethylation. Preoperative administration of S-adenosylmethionine (SAM) could hypomethylate the NR2B gene, upregulate NR2B expression and improve LTP, exerting a dose-dependent therapeutic effect against PND. Moreover, inhibiting NR2B abrogated the benefits of SAM pretreatment.

Conclusions: Laparotomy cause hippocampus-dependent cognitive decline by hypermethylating the NR2B gene, allowing us to understand the pathogenesis of PND in an epigenetic landscape.

Keywords

DNA methylation; NR2B; SAM; perioperative neurocognitive disorder.

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