Zhang Qian, Zhang Yuxin, Cong Peilin, Wu Qianqian, Wan Hanxi, Huang Xinwei, Li Xinyang, Li Zhouxiang, Li Jingxuan, Wu Huanghui, Tian Li, Xiong Lize
Shanghai 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, Department of Anesthesiology and Perioperative MedicineSchool of Medicine, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, 1239 Sanmen Road, Hongkou District, Shanghai, 200434, China.
Cell Mol Life Sci. 2025 Jan 6;82(1):37. doi: 10.1007/s00018-024-05530-7.
Perioperative neurocognitive disorder (PND) is a prevalent form of cognitive impairment in elderly patients following anesthesia and surgery. The underlying mechanisms of PND are closely related to perineuronal nets (PNNs). PNNs, which are complexes of extracellular matrix primarily surrounding neurons in the hippocampus, play a critical role in neurocognitive function. Connexin 43 (Cx43) contributes to cognitive function by modulating the components of PNNs. This study was designed to investigate the specific regulatory mechanisms of Cx43 on PNNs and its pivotal role in the development of PND.
Eighteen-month-old wild-type and Gja1 C57BL/6 mice were subjected to abdominal surgery under 1.4% isoflurane anesthesia. Cognitive functions, particularly learning and memory, were evaluated via the Y-maze test, Barnes maze (BM) and contextual fear conditioning test (CFT). The mRNA and protein expression levels of Cx43 were assessed by using quantitative reverse transcription polymerase chain reaction (qRT-PCR), fluorescent in situ hybridization (FISH), western blotting and flow cytometry. The quantity of PNNs was measured by Wisteria floribunda agglutinin (WFA) and Aggrecan staining.
Aged mice subjected to anesthesia and surgery exhibited deficits in hippocampus-dependent cognitive functions, which were accompanied by increased Cx43 mRNA and protein expression. Conditional knockout (cKO) of Cx43 in astrocytes alleviated cognitive deficits and promoted the number of PNNs and dendritic spines in the hippocampus by targeting Dmp1. Knockdown of Dmp1 attenuated the beneficial effects of Cx43 cKO on cognitive deficits induced by anesthesia and surgery.
Our findings indicate that anesthesia and surgery induce an increase in Cx43 expression, which inhibits the formation of PNNs and dendritic spines in hippocampus by suppressing Dmp1 transcription, leading to cognitive deficits in aged mice. These results offer new mechanistic insights into the pathogenesis of PND and identify potential targets for therapeutic intervention.
围手术期神经认知障碍（PND）是老年患者在麻醉和手术后常见的一种认知障碍形式。PND的潜在机制与神经元周围网络（PNNs）密切相关。PNNs主要是围绕海马体中神经元的细胞外基质复合物，在神经认知功能中起关键作用。连接蛋白43（Cx43）通过调节PNNs的成分来促进认知功能。本研究旨在探讨Cx43对PNNs的具体调控机制及其在PND发生发展中的关键作用。
18月龄的野生型和Gja1 C57BL/6小鼠在1.4%异氟烷麻醉下接受腹部手术。通过Y迷宫试验、巴恩斯迷宫（BM）和情境恐惧条件反射试验（CFT）评估认知功能，特别是学习和记忆能力。使用定量逆转录聚合酶链反应（qRT-PCR）、荧光原位杂交（FISH）、蛋白质免疫印迹法和流式细胞术评估Cx43的mRNA和蛋白表达水平。通过紫藤凝集素（WFA）和聚集蛋白聚糖染色测量PNNs的数量。
接受麻醉和手术的老年小鼠表现出海马体依赖的认知功能缺陷，同时伴有Cx43 mRNA和蛋白表达增加。星形胶质细胞中Cx43的条件性敲除（cKO）通过靶向Dmp1减轻了认知缺陷，并增加了海马体中PNNs和树突棘的数量。敲低Dmp1减弱了Cx43 cKO对麻醉和手术诱导的认知缺陷的有益作用。
我们的研究结果表明，麻醉和手术诱导Cx43表达增加，通过抑制Dmp1转录抑制海马体中PNNs和树突棘的形成，导致老年小鼠认知缺陷。这些结果为PND的发病机制提供了新的机制见解，并确定了治疗干预的潜在靶点。
