Putative complement control protein CSMD3 dysfunction impairs synaptogenesis and induces neurodevelopmental disorders

Recent studies have reported that complement-related proteins modulate brain development through regulating synapse processes in the cortex. CSMD3 belongs to a group of putative complement control proteins. However, its role in the central nervous system and synaptogenesis remains largely unknown. Here we report that CSMD3 deleterious mutations occur frequently in patients with neurodevelopmental disorders (NDDs). Csmd3 is predominantly expressed in cortical neurons of the developing cortex. In mice, Csmd3 disruption induced retarded development and NDD-related behaviors. Csmd3 deficiency impaired synaptogenesis and neurogenesis, allowing fewer neurons reaching the cortical plate. Csmd3 deficiency also induced perturbed functional networks in the developing cortex, involving a number of downregulated synapse-associated genes that influence early synaptic organization and upregulated genes related to immune activity. Our study provides mechanistic insights into the endogenous regulation of complement-related proteins in synaptic development and supports the pathological role of CSMD3 in NDDs.