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Updated: Jun 4, 2025
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Published on: February 27, 2018
DNMT3a Deficiency Contributes to Anesthesia/Surgery-Induced Synaptic Dysfunction and Cognitive Impairment in Aged
Peilin Cong1, Xinwei Huang1, Qian Zhang1
1Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
DNA methyltransferase 3a (DNMT3a) reduction in aged mice brains contributes to postoperative neurocognitive disorder (PND). Restoring DNMT3a levels may offer a therapeutic strategy for PND.
Area of Science:
- Neuroscience
- Epigenetics
- Gerontology
Background:
- Perioperative neurocognitive disorder (PND) is a significant complication in elderly patients post-surgery.
- Epigenetic alterations are linked to aging and cognitive decline, but their role in PND is not fully understood.
Purpose of the Study:
- To investigate the role of epigenetic mechanisms, specifically DNA methyltransferase 3a (DNMT3a), in the development of PND in aged mice.
- To elucidate the molecular pathways linking anesthesia/surgery to cognitive impairment in the aging brain.
Main Methods:
- A laparotomy model was used to induce PND in aged mice.
- DNA methyltransferase 3a (DNMT3a) levels, global DNA methylation, and LRG1 promoter methylation were assessed.
- Synaptic function and memory were evaluated in mice with altered DNMT3a or LRG1 expression.
- Bisulfite sequencing and TGF-β signaling pathway analysis were performed.
Main Results:
- Aged mice with PND exhibited reduced hippocampal DNMT3a, leading to decreased global DNA methylation.
- DNMT3a knockdown in aged mice resulted in synaptic dysfunction and memory deficits.
- DNMT3a deficiency reduced methylation at the LRG1 promoter, increasing LRG1 transcription and activating TGF-β signaling.
- Overexpressing DNMT3a or reducing LRG1 expression ameliorated synaptic issues and rescued cognitive deficits.
Conclusions:
- DNMT3a acts as a critical mediator in PND pathogenesis by linking epigenetic dysregulation to anesthesia/surgery-induced synaptic dysfunction.
- Targeting DNMT3a or LRG1 presents a potential therapeutic avenue for preventing and treating PND in the elderly.
