Transient neuroinflammation following surgery contributes to long-lasting cognitive decline in elderly rats via dysfunction of synaptic NMDA receptor

作者全名："Chen, Bo; Qin, Guangcheng; Xiao, Jingyu; Deng, Xiaoyuan; Lin, Aolei; Liu, Hongliang"

作者地址："[Chen, Bo; Xiao, Jingyu; Deng, Xiaoyuan; Liu, Hongliang] Chongqing Univ, Canc Hosp, Dept Anesthesiol, Chongqing 400030, Peoples R China; [Qin, Guangcheng] Chongqing Med Univ, Affiliated Hosp 1, Lab Res Ctr, Chongqing 400016, Peoples R China; [Lin, Aolei] Chongqing Med Univ, Affiliated Hosp 1, Dept Neurol, Chongqing 400016, Peoples R China"

通信作者："Liu, HL (通讯作者)，Chongqing Univ, Canc Hosp, Dept Anesthesiol, Chongqing 400030, Peoples R China."

来源：JOURNAL OF NEUROINFLAMMATION

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:000824627400001

JCR分区：Q1

影响因子：9.3

年份：2022

卷号：19

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Postoperative cognitive dysfunction; Neuroinflammation; NMDAR; structural plasticity; Rac1

摘要："Background Perioperative neurocognitive disorders (PNDs) are considered the most common postoperative complication in geriatric patients. However, its pathogenesis is not fully understood. Surgery-triggered neuroinflammation is a major contributor to the development of PNDs. Neuroinflammation can influence N-methyl-D-aspartate receptor (NMDAR) expression or function which is closely associated with cognition. We, therefore, hypothesized that the persistent changes in NMDAR expression or function induced by transient neuroinflammation after surgery were involved in the development of PNDs. Methods Eighteen-month-old male Sprague-Dawley rats were subjected to abdominal surgery with sevoflurane anesthesia to establish the PNDs animal model. Then, we determined the transient neuroinflammation by detecting the protein levels of proinflammatory cytokines and microglia activation using ELISA, western blot, immunohistochemistry, and microglial morphological analysis from postoperative days 1-20. Persistent changes in NMDAR expression were determined by detecting the protein levels of NMDAR subunits from postoperative days 1-59. Subsequently, the dysfunction of synaptic NMDAR was evaluated by detecting the structural plasticity of dendritic spine using Golgi staining. Pull-down assay and western blot were used to detect the protein levels of Rac1-GTP, phosphor-cofilin, and Arp3, which contribute to the regulation of the structural plasticity of dendritic spine. Finally, glycyrrhizin, an anti-inflammatory agent, was administered to further explore the role of synaptic NMDAR dysfunction induced by transient neuroinflammation in the neuropathogenesis of PNDs. Results We showed that transient neuroinflammation induced by surgery caused sustained downregulation of synaptic NR2A and NR2B subunits in the dorsal hippocampus and led to a selective long-term spatial memory deficit. Meanwhile, the detrimental effect of neuroinflammation on the function of synaptic NMDARs was shown by the impaired structural plasticity of dendritic spines and decreased activity of the Rac1 signaling pathways during learning. Furthermore, anti-inflammatory treatment reversed the downregulation and hypofunction of synaptic NR2A and NR2B and subsequently rescued the long-term spatial memory deficit. Conclusions Our results identify sustained synaptic NR2A and NR2B downregulation and hypofunction induced by transient neuroinflammation following surgery as important contributors to the development of PNDs in elderly rats."

基金机构："National Science Foundation Project of Chongqing [cstc2017jcyjBX0043, cstc2019jcyj-msxmX0608]; National Natural Science Foundation of China [NSFC82101282]"

基金资助正文：This study was supported by grants from the National Science Foundation Project of Chongqing (cstc2017jcyjBX0043 and cstc2019jcyj-msxmX0608). This study was also supported by grants from the National Natural Science Foundation of China (NSFC82101282).