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.

length: 244/250 Abstract 33 Background Recent findings implicate complement, a key component of the 34 immune system, in healthy brain functioning and risk for psychiatric disorders. 35Altered emotional function, in particular maladaptive fear and anxiety, is a pervasive 36 and clinically important symptom across several neuropsychiatric disorders. In this 37 work we examined the extent to which different complement pathways impact on 38 dissociable components of anxiety and learned fear. 39 Methods: C3 -/and C3aR -/mice were assessed in a battery of tests assaying innate 40 anxiety and learned fear. The effects of systemic diazepam (2mg/kg) and the C3aR 41 antagonist SB290157 (10mg/kg) on behaviour was assessed. Expression of genes 42 linked to anxiety, stress responses and risk for psychiatric disorder were assessed in 43 brain regions implicated in fear and anxiety. 44 Results: The data indicated a robust and highly reproducible double-dissociation of 45 C3 and C3aR on learned fear and innate anxiety, respectively. We probed 46 downstream complement pathways responsible for the C3-specific effects on 47 Conclusions: These findings reveal novel functions and unexpected dissociations 55between the C3 and C3aR pathways impacting on specific emotional behaviours 56 relevant to psychiatric disorder.

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