Complement receptor C3ar1 deficiency does not alter brain structure or functional connectivity across early life development

Lemmik, H.; Kim, E.; MacNicol, E.; Maselli, D.; Bernanos, M.; Li, Z.; Abdullahi, D.; Walters, E.; Serrano Navacerrada, M. E.; Zhou, W.; Ivetic, A.; Cash, D.; Westacott, L.

doi:10.1101/2025.04.24.650541

bioRxiv · 10.1101/2025.04.24.650541

Complement receptor C3ar1 deficiency does not alter brain structure or functional connectivity across early life development

Lemmik, H.·Kim, E.·MacNicol, E.·Maselli, D.·Bernanos, M.·Li, Z.·Abdullahi, D.·Walters, E.·Serrano Navacerrada, M. E.·Zhou, W.·Ivetic, A.·Cash, D.·Westacott, L.

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Abstract

Genetic deletion of the complement C3a anaphylatoxin chemotactic receptor (C3ar1), a key component of the innate immune response, is reported to induce behavioural phenotypes consistent with psychiatric symptomatology in mice, but when and where C3ar1 is needed in the brain is unresolved. These questions are significant because, as a G-protein-coupled receptor, human C3AR1 serves as a potential therapeutic target for disorders associated with complement dysregulation, such as schizophrenia. To provide a brain-wide (where) assessment of developmental C3ar1 activity, we used longitudinal (when) tensor-based morphometry, diffusion-weighted magnetic resonance imaging (MRI) and blood oxygen-level dependent functional MRI in male and female C3ar1-deficient mice and wild-type littermates, with behavioural assessment in adulthood. Unexpectedly, we did not find a robust C3ar1-dependent phenotype in any of these measures. Therefore, our study does not support neurodevelopmental hypotheses for C3ar1, which is encouraging for therapeutic strategies targeting this receptor since interventions are unlikely to disrupt brain development.

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Lemmik, H., Kim, E., MacNicol, E., Maselli, D., Bernanos, M., Li, Z., Abdullahi, D., Walters, E., Serrano Navacerrada, M. E., Zhou, W., Ivetic, A., Cash, D., Westacott, L.. 2025-04-26. Complement receptor C3ar1 deficiency does not alter brain structure or functional connectivity across early life development. https://doi.org/10.1101/2025.04.24.650541

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