Prolonged anesthesia induces neuroinflammation and complement-mediated microglial synaptic elimination involved in neurocognitive dysfunction and anxiety-like behaviors

Abstract

Background Perioperative neurocognitive disorders (PND) with a high incidence frequently occur in elderly surgical patients closely associated with prolonged anesthesia-induced neurotoxicity. The neuromorphopathological underpinnings of anesthesia-induced neurotoxicity have remained elusive. Methods Prolonged anesthesia with sevoflurane was used to establish the sevoflurane-induced neurotoxicity (SIN) animal model. Morris water maze, elevated plus maze, and open field test were employed to track SIN rats’ cognitive behavior and anxiety-like behaviors. We investigated the neuropathological basis of SIN through techniques such as transcriptomic, electrophysiology, molecular biology, scanning electron microscope, Golgi staining, TUNEL assay, and morphological analysis. Our work further clarifies the pathological mechanism of SIN by depleting microglia, inhibiting neuroinflammation, and C1q neutralization. Results This study shows that prolonged anesthesia triggers activation of the NF-κB inflammatory pathway, neuroinflammation, inhibition of neuronal excitability, cognitive dysfunction, and anxiety-like behaviors. RNA sequencing found that genes of different types of synapses were downregulated after prolonged anesthesia. Microglial migration, activation, and phagocytosis were enhanced. Microglial morphological alterations were also observed. C1qa, the initiator of the complement cascade, and C3 were increased, and C1qa tagging synapses were also elevated. Then, we found that the “Eat Me” complement pathway mediated microglial synaptic engulfment in the hippocampus after prolonged anesthesia. Afterward, synapses were remarkably lost in the hippocampus. Furthermore, dendritic spines were reduced, and their genes were also downregulated. Depleting microglia ameliorated the activation of neuroinflammation and complement and rescued synaptic loss, cognitive dysfunction, and anxiety-like behaviors. When neuroinflammatory inhibition or C1q neutralization occurred, complement was also decreased, and synaptic elimination was interrupted. Conclusions These findings illustrated that prolonged anesthesia triggered neuroinflammation and complement-mediated microglial synaptic engulfment that pathologically caused synaptic elimination in SIN. We have demonstrated the neuromorphopathological underpinnings of SIN, which have direct therapeutic relevance for PND patients.

Complement C1q-mediated microglial synaptic elimination by enhancing desialylation underlies sevoflurane-induced developmental neurotoxicity

“…Second, the electrophysiology of synapses such as long-term potentiation/depression, EEG changes, or burst suppression was not measured. Previous studies have demonstrated that sevoflurane impaired synapse development and electrophysiological activity [ 23 , 61 – 64 ]. Last, we used intraperitoneal injection of ANX005 and NADNA to inhibit the expression of C1q and sialidase respectively, and we did not perform interventions at the gene and transcriptional levels.…”

“…C1q is the initiating protein in the complement cascade. A recent study showed that prolonged sevoflurane exposure increased C1q expression in the rat hippocampus, and deletion of C1q prevented microglial synaptic engulfment to alleviate cognitive dysfunction [ 23 ]. Several factors affect the binding of C1q to synapses, such as CD47, neuronal pentraxins, and sialic acids [ 24 ].…”

Reactive gliosis in traumatic brain injury: a comprehensive review

“…Drugs used for induction of general anesthesia, such as isoflurane, suppress LPS-induced expression of microglial pro-inflammatory cytokine IL-1β in mouse brains ( Tanaka et al, 2013 ). On the other hand, prolonged anesthesia using sevoflurane induces neuroinflammation by triggering the NF-κB pathway, activates microglia, and alters their morphology in the hippocampus of aged rats ( Xu et al, 2023 ). According to Brambrink et al (2012) , exposure to isoflurane for 5 h causes apoptosis of oligodendrocytes (estimated at 6.3% of the total oligodendrocyte population) in neonatal primate brains ( Brambrink et al, 2012 ).…”

Intertwined associations between oxytocin, immune system and major depressive disorder

“…Under physiological conditions, microglia play a crucial role in the process of synaptic pruning, which maintains the integrity of neural circuits. However, under pathological conditions, activated microglia can lead to excessive synaptic phagocytosis, resulting in the loss of synapses and consequent cognitive impairment [135] , [136] , [137] . In mice with chronic social defeat stress-induced depression, there is evidence of excessive synaptic pruning, which is attributed to microglia-dependent synaptic phagocytosis [138] .…”