Recent studies have found non-immunological roles of the classical complement pathway (CP) in brain development and its involvement in neuropsychiatric and neurodegenerative diseases. However, multiple complement activation pathways exist beyond the CP, but their expression and function remain poorly understood in the brain. Using MERFISH, we constructed a comprehensive spatial transcriptomic atlas of the complement system in mouse brains from the late embryonic stage to adulthood. Here, we show that most complement genes are expressed locally with a remarkable degree of cellular, spatial, and temporal heterogeneity and that complement regulatory mechanisms are distinct from the periphery. Beyond confirming the known expression of the CP, our measurements reveal endogenous expression of the alternative pathway (AP), notably the AP activator Masp3 in immature brains. Masp3 deficiency causes working spatial memory defects and altered molecular structure of the brain, indicating a role of Masp3 in brain maturation, potentially via modulation of AP activity.

Funding provided by: National Institute of Mental HealthROR ID: https://ror.org/04xeg9z08Award Number: P50MH112491 Funding provided by: National Institute of General Medical SciencesROR ID: https://ror.org/04q48ey07Award Number: R01GM143277

Spatial transcriptomic data were collected using MERFISH in p5 and p60 wild-type mouse brain sagittal sections.