LAUSR

Background: The complement system is a key effector of innate immunity, mediating elimination of pathogens and debris via initiation of phagocytosis, inflammation, and cell lysis. Intriguingly, recent studies have identified an additional role for early complement components, including C1q, C3, and C4, in synaptic pruning and remodeling. Mounting evidence suggests that dysregulation of the complement system occurs in schizophrenia. Increased activation and concentration of complement components has been reported in blood, while complement C4 was recently identified as a major genetic risk factor. However, little is known about expression of complement components in brain tissue in this disorder. The aim of this study was therefore to compare protein and mRNA expression of early complement components in frontal cortex in schizophrenia and control subjects. Methods: Protein and/or mRNA expression of the early complement components C1q, C3 and C4, and the regulator C1-inhibitor, was quantified in 35 individuals with SCZ and 35 controls. Samples were obtained from the orbital–frontal and dorsolateral prefrontal regions courtesy of the Stanley Medical Research Institute. Proteins were quantified in dorsolateral prefrontal cortex by immunoblotting, and mRNA expression measured in orbital–frontal cortex using quantitative PCR. Measures were compared between groups using analysis of variance. Results: C1-inhibitor was higher in the schizophrenia group. While C4 mRNA expression was increased in schizophrenia, C4 protein levels did not differ between groups, despite the presence of a positive correlation between protein and mRNA expression. Of note, C4 genotype was associated with C4 protein levels. Furthermore, C4 protein levels were negatively correlated with levels of the synaptic protein SNAP-25. Finally, positive correlations were observed between early complement components and markers of peripheral and/or central inflammation. Conclusion: Overall, our results are consistent with a dysregulation of the complement system in schizophrenia. Increased complement expression may be indicative of an inflammatory response. However, early complement components have also been implicated in synaptic pruning and circuit remodeling. Observed correlations between complement C4 and SNAP-25 suggest the complement system may play a role in triggering the synaptic disturbances previously identified in schizophrenia. Funding: This work was supported by the Canadian Institutes of Health Research.