Dissociable effects of complement C3 and C3aR on survival and morphology of adult born hippocampal neurons, pattern separation, and cognitive flexibility in male mice

•Complement C3 negatively regulates the survival and migration of adult born hippocampal neurons, independent of C3a/C3aR signalling.•Complement C3aR is required for normal morphological development of immature neuronal progenitors in the adult hippocampal niche.•Lack of C3 impairs behavioural inhibition and cognitive flexibility.•Lack of C3aR enhances pattern separation without impacting cognitive flexibility. Adult hippocampal neurogenesis (AHN) is a form of ongoing plasticity in the brain that supports specific aspects of cognition. Disruptions in AHN have been observed in neuropsychiatric conditions presenting with inflammatory components and are associated with impairments in cognition and mood. Recent evidence highlights important roles of the complement system in synaptic plasticity and neurogenesis during neurodevelopment and in acute learning and memory processes. In this work we investigated the impact of the complement C3/C3aR pathway on AHN and its functional implications for AHN-related behaviours. In C3−/− mice, we found increased numbers and accelerated migration of adult born granule cells, indicating that absence of C3 leads to abnormal survival and distribution of adult born neurons. Loss of either C3 or C3aR affected the morphology of immature neurons, reducing morphological complexity, though these effects were more pronounced in the absence of C3aR. We assessed functional impacts of the cellular phenotypes in an operant spatial discrimination task that assayed AHN sensitive behaviours. Again, we observed differences in the effects of manipulating C3 or C3aR, in that whilst C3aR−/− mice showed evidence of enhanced pattern separation abilities, C3−/− mice instead demonstrated impaired behavioural flexibility. Our findings show that C3 and C3aR manipulation have distinct effects on AHN that impact at different stages in the development and maturation of newly born neurons, and that the dissociable cellular phenotypes are associated with specific alterations in AHN-related behaviours.