Complement C3 and C3aR differentially impact on learned fear and innate anxiety

Abstract Recent findings implicate complement, a key component of the innate immune system, in brain function and risk for neuropsychiatric disorders. We reveal novel functions and unexpected dissociations of complement pathways impacting on emotional behaviours. First, we showed profound anxiety phenotypes, indexed by behaviour and physiological measures, in C3aR-/- mice but not C3-/- mice across several tests of innate anxiety. Administration of the C3aR antagonist SB290157 did not phenocopy C3aR-/- mice, consistent with C3aR knockout influencing adult behaviour via developmental mechanisms. In contrast to the findings on innate anxiety, C3-/- mice, but not C3aR-/- mice, showed behaviour indicative of greater learned fear. We probed downstream complement pathways responsible for the C3-specific effects on learned fear and excluded contributions from the terminal pathway, C6 to C9. Our data provide evidence for dissociable effects of complement pathways in aspects of affective function relevant to psychiatric disorder.