The Role Of “Complement-microglial Axis”-Mediated Synaptic Remodeling In LPS-induced Systemic Inflammation Related Cognitive Impairment

Objective: Systemic inflammation induces cognitive impairment via unclear mechanism.Increasing evidence has suggested complement C3/C3 a receptor signaling,a key component of innate immune pathogen defense,plays an important role in cognition and neurodegeneration,whereas its dysfunction is implicated in many neurological disorders.However,it remains unclear whether complement C3/C3 a receptor signaling was involved in systemic inflammation-induced cognitive impairment.The purpose of the study is to investigate the changes of complement C3/C3 a receptor signaling pathways and synaptic-related proteins in the brain by establishing the animal model of lipopolysaccharide(LPS)induced cognitive dysfunction.Moreover,the role and mechanism of complement C3/C3 a receptor signaling pathways in LPS-induced cognitive dysfunction are explored.Methods: In the present study,we used LPS(lipopolysaccharide,2 mg/kg,i.p.injection) induced endotoxin sepsis model to investigate the role of C3/C3 a R signaling in adult male C57BL/6 mice.12-14 week old mice are randomly divided into five groups(n = 10): saline group(NS group),lipopolysaccharide group(LPS group),saline + dimethyl sulfoxide group(NS + DMSO group),lipopolysaccharide + dimethyl sulfoxide group(LPS + DMSO group),lipopolysaccharide + C3 a receptor antagonist group(LPS + C3 a Ra group).Complement C3 expression was assessed in the hippocampus by liquid chromatography-tandem mass spectrometry(LC–MS/MS)and western blot.Changes in hippocampal neuroinflammation(i.e.,microglia activation and inflammatory cytokines),excitatory/inhibitory synapse related proteins,and hippocampal-dependent memory function were evaluated after LPS and treatment with a C3 a receptor blocker.Results: In the present study,we identified complement C3 was markedly up-regulated in hippocampus of LPS group in comparison to control mice(P < 0.05),meanwhile we showed that hippocampal complement C3 levels and C3 a receptor expressions were specifically upregulated in astrocytes and microglia after lipopolysaccharide(LPS)injection(P < 0.05). Interestingly,LPS selectively induced inhibitory(VGAT,GAD65/67,gephyrin)but not excitatory(VGLUT1,synaptophysin(SYP),PSD-95)synapse related protein loss(P < 0.05).Notably,C3 a receptor antagonist SB290157 trifluoroacetate attenuated LPS-induced hippocampal neuroinflammation and inhibitory synapse related protein loss(P < 0.05),contributing to improved cognitive function(fear conditioning test,Y-maze)(P < 0.05).Conclusion: Our research suggests that loss of inhibitory synapse-related proteins mediated by“complement C3-microglia axis” after LPS injection may lead to cognitive dysfunction.The administration of C3 a receptor antagonists can effectively reduce the loss of inhibitory synapserelated proteins and improve cognitive performance.