ROLE OF TYPE I INTERFERON RECEPTOR IN BRAIN DEVELOPMENT

Type I interferons are best known for their roles in innate immunity, yet increasing evidence indicates that their functions extend beyond host defense. Previous work from our group demonstrated that signaling through the type I interferon receptor (IFNAR) in astrocytes modulates hippocampal synaptic plasticity and cognitive function in adult mice under physiological conditions. Given the involvement of cytokines in neurogenesis and brain development, the present study investigated the contribution of IFNAR signaling in the developing CNS. We analyzed 3-week-old conventional IFNAR knockout (KO) mice and respective cell type-specific knockout models targeting astrocytes (IFNAR^fl/fl GFAPCre^+/-) or neurons (IFNAR^fl/fl SynCre^+/-). Golgi-Cox staining revealed a sex-specific reduction in dendritic spine density in the hippocampal CA1 region of female IFNAR knockout (KO) mice. This phenotype recapitulated in astrocyte-specific IFNAR KOs, but not in males or neuron-specific knockouts. In the dentate gyrus, loss of type I interferon signaling led to significantly reduced spine density in both sexes. Single-cell analyses of microglia and astrocytes further indicated altered synaptic pruning in both CA1 and the dentate gyrus, with distinct sex- and cell type–dependent effects. Consistent with these findings, loss of type I interferon signaling also altered microglial and astrocytic phagocytic function. Collectively, these data identify a critical physiological role for IFNAR signaling in brain development, particularly in developmental synaptic pruning, and reveal previously unrecognized sex-specific and cell type-specific consequences of this pathway.