<scp>DNMT3a</scp> Deficiency Contributes to Anesthesia/Surgery‐Induced Synaptic Dysfunction and Cognitive Impairment in Aged Mice

Perioperative neurocognitive disorder (PND) is a severe postoperative complication in older patients. Epigenetic changes are hallmarks of senescence and are closely associated with cognitive impairment. However, the effects of anesthesia and surgery on the aging brain's epigenetic regulatory mechanisms and its impact on cognitive impairment remain unclear. Using a laparotomy PND model, we report significant reduction in DNA methyltransferase 3a (DNMT3a) in hippocampal neurons of aged mice, which causes global DNA methylation decrease. Knockdown of DNMT3a leads to synaptic disorder and memory impairment in aged mice. Mechanistically, bisulfite sequencing revealed that DNMT3a deficiency reduces methylation in the LRG1 promoter region and promotes its transcription. We also show that activation of TGF-β signaling by the increase in LRG1 level, ultimately impacts the synaptic function. In contrast, both overexpressing DNMT3a or knockdown LRG1 in hippocampus can attenuate the synaptic disorders and rescue postoperative cognitive deficits in aged mice. Our results reveal that DNMT3a is a previously undefined mediator in the pathogenesis of PND, which couples epigenetic regulations with anesthesia/surgery-induced synaptic dysfunction and represents a therapeutic target to tackle PND.