The role of Complement C3 in the neurodevelopment of central nervous system

Abstract

Recent studies highlighted the role of complement C3 on neurogenesis, neuro-migration, and synaptic refinement, which are essential steps for normal brain development. Here we aimed to holistically reveal the role of complement C3 in neurodevelopment within the central nervous system. We applied multiplexed error-robust fluorescence in situ hybridization (MERFISH) to generate quantitative, spatially resolved RNA transcriptomics in a C3 deficient mouse model at two different ages, P5 and P40. This high throughput technology enabled us to compare RNA expression levels and spatial distributions for hundreds of neuronal and complement genes in the brain between C3 deficient and wild type mice on a single cell level during development. Intriguingly, we found that a group of SIRPα positive excitatory neurons in the thalamus region is absent in C3 deficient mice, compared to their wild type counterparts at P40. Previous literatures have shown that SIPRa-CD47 interaction in excitatory neurons is essential for pre-synaptic maturations. The reduced SIRPα level in C3 deficient mice may lead to lowered levels of highly functional synapses and thus reduced brain functions. The results suggested that C3 activity in the brain is essential for synapse development not just by mediating microglial-dependent synaptic pruning, but also by regulating the expression of the neurotrophic receptor that can directly affect synaptic maturation.