Different complement immune pathways mediate innate anxiety and learned fear

Complement is a key component of the immune system with roles in inflammation and host-defence. Here we reveal unanticipated functions of complement pathways impacting on emotional reactivity of 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. C3aR-/- mice demonstrated a selective increase in unconditioned (innate) anxiety whilst C3-/- mice 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, indicating 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.