Complement C3 and C3aR mediate different aspects of emotional behaviours; relevance to risk for psychiatric disorder

• Published in: Brain, behavior, and immunity behavior, and immunity, 2022-01, Vol.99, p.70-82
• Main Authors: Westacott, Laura J., Humby, Trevor, Haan, Niels, Brain, Sophie A., Bush, Emma-Louise, Toneva, Margarita, Baloc, Andreea-Ingrid, Moon, Anna L., Reddaway, Jack, Owen, Michael J., Hall, Jeremy, Hughes, Timothy R., Morgan, B. Paul, Gray, William P., Wilkinson, Lawrence S.
• Format: Article
• Language: English
• Subjects: Animals; Anxiety; Complement C3 - genetics; Complement C3 - metabolism; Complement system; Disease Models, Animal; Fear; Inflammation; Mental Disorders; Mice; Receptors, Complement; Signal Transduction; Stress response
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2021.09.005

•There is increasing evidence for a role of the complement system in psychiatric disorders.•We report a double dissociation of the roles of specific complement proteins in innate anxiety and learned fear.•The effects of C3aR deletion on innate anxiety appeared to be independent from the canonical C3aR signaling partner C3a.•Mice lacking C3 showed perturbed learned fear responses likely due to loss of C3b/CR3 signalling.•Complement may be linked to a family of genes mediating calcium signaling implicated in polygenic risk for psychiatric disorders. Complement is a key component of the immune system with roles in inflammation and host-defence. Here we reveal novel functions of complement pathways impacting on emotional reactivity of potential relevance to the emerging links between complement and risk for psychiatric disorder. We used mouse models to assess the effects of manipulating components of the complement system on emotionality. Mice lacking the complement C3a Receptor (C3aR−/−) demonstrated a selective increase in unconditioned (innate) anxiety whilst mice deficient in the central complement component C3 (C3−/−) showed a selective increase in conditioned (learned) fear. The dissociable behavioural phenotypes were linked to different signalling mechanisms. Effects on innate anxiety were independent of C3a, the canonical ligand for C3aR, consistent with the existence of an alternative ligand mediating innate anxiety, whereas effects on learned fear were due to loss of iC3b/CR3 signalling. Our findings show that specific elements of the complement system and associated signalling pathways contribute differentially to heightened states of anxiety and fear commonly seen in psychopathology.