Complement activation contributes to perioperative neurocognitive disorders in mice

Abstract

BackgroundThe complement system plays an important role in many neurological disorders.Complement modulation, including C3/C3a receptor signaling, shows promising therapeutic effects on cognition and neurodegeneration. Yet, the implications for this pathway in perioperative neurocognitive disorders (PND) are not well established. Here, we evaluated the possible role for C3/C3a receptor signaling after orthopedic surgery using an established mouse model of PND.MethodsA stabilized tibial fracture surgery was performed in adult male C57BL/6 mice under general anesthesia and analgesia to induce PND-like behavior. Complement activation was assessed in the hippocampus and choroid plexus. Changes in hippocampal neuroinflammation, synapse numbers, choroidal blood-cerebrospinal fluid barrier (BCSFB) integrity, and hippocampal-dependent memory function were evaluated after surgery and treatment with a C3a receptor blocker.ResultsC3 levels and C3a receptor expression were specifically increased in hippocampal astrocytes and microglia after surgery. Surgery-induced neuroinflammation and synapse loss in the hippocampus were attenuated by C3a receptor blockade. Choroidal BCSFB dysfunction occurred 1 day after surgery and was attenuated by C3a receptor blockade. Administration of exogenous C3a exacerbated cognitive decline after surgery, whereas C3a receptor blockade improved hippocampal-dependent memory function.ConclusionsOrthopedic surgery activates complement signaling. C3a receptor blockade may be therapeutically beneficial to attenuate neuroinflammation and PND.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1292-4) contains supplementary material, which is available to authorized users.

Sex Differences of Microglia and Synapses in the Hippocampal Dentate Gyrus of Adult Mouse Offspring Exposed to Maternal Immune Activation

“…Interestingly, C3 levels in our data were increased in GFAP+ astrocytes. Astrocytic C3 production may modulate synaptic density, as observed in models of Alzheimer's disease (Lian et al, 2015(Lian et al, , 2016Luchena et al, 2018), amyotrophic lateral sclerosis (Heurich et al, 2011), perioperative neurocognitive disorder (Xiong et al, 2018) and diabetes (Zhao et al, 2018). We now show that there may be a similar phenomenon in the mIA model of schizophrenia.…”

IL-17A contributes to perioperative neurocognitive disorders through blood-brain barrier disruption in aged mice

“…And the immunity plays an important role in maintaining the function of the blood-brain barrier. Peripheral surgery may disrupt the BBB via complement activation and pro-inflammatory cytokines, such as TNF-α and high mobility group box-1 (HMGB1), which promotes brain inflammation [ 50 , 51 ]. Furthermore, BBB disruption facilitates the migration of macrophages into the brain, and the hippocampal recruitment of macrophages is necessary for neuroinflammation and memory dysfunction, inducing cognitive decline following surgery [ 52 , 53 ].…”

Cerebrospinal Fluid Proteomic Changes in Older Non-Cardiac Surgical Patients with Postoperative Cognitive Dysfunction

“…Pathway analysis on peptides that showed trend-level signi cance with q < 0.25 identi ed a signi cant role for the complement and coagulations factors pathway(s). The hypothesis that complement plays a role in perioperative neurocognitive disorders aligns with current animal models of surgery-induced neuroin ammation and cognitive decline [62]. Complement regulates brain development and homeostasis by driving microglial synaptic phagocytosis [63], and in murine models, complement-dependent synaptic pruning is critical for optimizing cognitive performance by reducing excessive synapse numbers that can cause epilepsy [64,65].…”

“…A role for complement in perioperative neurocognitive disorders would t the theory that these disorders are driven by neuroin ammation [1,69]. Indeed, murine model studies have shown that complement C3 levels, an initiator of the complement cascade, and levels of the receptor for its cleavage product (C3aR) are elevated after orthopedic surgery, and these increases have been shown to contribute to cognitive dysfunction in mouse POCD models [62]. Similarly, elevated baseline CSF C3 levels have been associated with higher rates of postoperative delirium in human patients [70], and critically-ill patients with delirium have been found to exhibit upregulated CSF complement levels [71].…”