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

Abstract

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.

RETRACTED: Young plasma reverses anesthesia and surgery-induced cognitive impairment in aged rats by modulating hippocampal synaptic plasticity

“…Recently, numerous studies have reported that young plasma reduces the spontaneous cognitive function of aged rats by improving hippocampal synaptic plasticity ( Gao et al, 2021 ; Chen et al, 2022 ; Xue et al, 2022 ). Given that the mechanism of cognitive function impairment during the aging process is similar to that following surgery and that the disruption of synaptic plasticity is also an important mechanism in the occurrence and development of postoperative cognitive impairment in older adults, we predicted that pre-infusion of young plasma would reduce the occurrence of POCD by improving hippocampal synaptic plasticity.…”

Acute exposure of microwave impairs attention process by activating microglial inflammation

“…Noted, that glutamatergic NMDAR plays a central role in PFC activity and its cognitive functions such as working memory, attention and reversal learning (20)(21)(22)(23). In addition, NMDAR is also associated with in ammation (53,54), and previous study demonstrate a remarkable increase in NMDA (NR2A and C) mRNA expression after viral-like brain in ammation (53). Here, we observed poor performance of mice in 5-CSRT after MW exposure with increased omissions and decreased correct responses accompanied by elevated expression of NMDAR (NR2A and NR2B).…”

Vitamin D3 Supplementation Attenuates Surgery-Induced Neuroinflammation and Cognitive Impairment by Regulating NLRP3 Inflammasome in Mice

“…Throughout the past decades, surgery-related cognitive impairment has been linked to neuroinflammation. A major factor in the development of cognitive impairment has been proposed to be the release of proinflammatory cytokines [ 18 , 23 , 24 ]. It has been demonstrated that the neuroinflammatory response during POCD pathophysiology is affected by variations in the levels of proinflammatory cytokines in the cerebrospinal fluid of postoperative patients.…”