Different complement immune pathways mediate innate and learned aversion

Complement is a key component of the immune system. Here we show that complement pathways with canonical roles in inflammation and host defence also impact on emotional responses to aversive events in a highly selective manner. Using mouse models deficient in a panel of complement proteins and focusing on the central role of C3 in complement signalling, we first demonstrated that C3aR deletion markedly increased physiological and behavioural responses to innate anxiety-provoking stimuli. These effects, which were resistant to benzodiazepines, drugs used in the treatment of anxiety, were independent of C3a the ligand for C3aR, indicating the existence of an alternative C3aR ligand mediating anxiety responses. In contrast, manipulation of C3aR had no influence on learned fear, where a previously neutral cue generates a fear response as a result of predicting an aversive outcome. Instead increases in learned fear were found only as a consequence of C3 deletion and subsequent downstream disruption to iC3b/CR3 signalling, a complement pathway previously associated with synaptic plasticity via effects on synaptic elimination. Our findings indicate an unanticipated complexity and subtlety to the way in which particular complement proteins, acting through distinct signalling pathways, can influence emotional dysfunction of relevance to many common psychopathologies, as such they add evidence to the emerging links between complement and risk for psychiatric disorder.