An Atlas of the Complement System in Developing and Adult Mouse Brains

Abstract

Abstract The complement system is traditionally known as a key pathway of peripheral innate immunity. Recent studies reveal distinct functions of the complement system in normal development of mammalian central nervous system (CNS). Over activation of the complement system has been associated with increased risks for Schizophrenia in humans by causing excessive synapse pruning. However, the source of complement and its regulation in the CNS remains largely unknown. To this end, we applied MERFISH (Multiplexed Error Robust Fluorescent in <underline>s</underline>itu Hybridization), a novel spatial transcriptomic approach, to establish a brain atlas of the complement system during development. We found that most components of the complement pathway are locally expressed in the brain. They are expressed by particular types of cells in the brain with distinct spatial and temporal distribution. Notably, the lectin pathway showed striking age-dependent differences in expression level and spatial heterogeneity in the brain. Moreover, suggesting an active role of complement in brain development, we found the spatial distribution of a subset of complement regulatory genes coincides with that of neural development-related genes in the cerebral cortex. To further investigate this hypothesis, we are currently studying the effect of complement inactivation on CNS development by comparing neuronal populations from wild type mice to those with C3 or C4 deficiency. Ultimately, we aim to use our approach to understand molecular changes and abnormalities in CNS development caused by overactivation of the complement cascade, and how these changes increase risks for developing Schizophrenia. This work is supported by the Conte Center Grant NIH 1P50MH112491.