Complement C3 mediates adolescent social isolation‐induced hippocampal synaptic deficits and sex‐specific emotional dysfunction

Abstract Social isolation during adolescence is a critical risk factor for negative emotional symptoms, yet its neurobiological mechanisms remain incompletely understood. Here, we integrate human and mouse data to investigate the behavioral, functional, and molecular consequences of social isolation across development. In humans from the Human Connectome Project in Development, reduced social connectedness was robustly associated with greater depressive and anxiety symptoms across adolescence, with sex‐specific patterns in effect distribution. At the neural level, social experience was preferentially associated with alterations in hippocampal functional connectivity (FC) rather than gross structure, and exhibited sex‐ and hemisphere‐dependent coupling with large‐scale cortical networks. In parallel, adolescent mice exposed to chronic social isolation exhibited marked reductions in hippocampal synaptic density and calcium signaling, accompanied by astrocyte‐associated upregulation of complement components C3 and complement factor properdin and enhanced complement‐mediated microglial synaptic pruning. Genetic deletion of C3 rescued synaptic deficits and alleviated depressive‐like behaviors. Together, these findings identify a conserved neuroimmune pathway through which adolescent social isolation disrupts hippocampal FC, with sex‐ and species‐specific phenotypic expression across behavioral and neural levels, highlighting a sex‐specific mechanism linking social experience to neuropsychiatric risk.