REGULATION OF MICROGLIA BY SEROTONIN: IMPLICATIONS FOR THE MATURATION OF BRAIN CIRCUITS

Microglia play a key role in postnatal brain development by shaping neuronal circuits through synaptic remodeling, and dysregulation of microglial functions leads to neuronal connectivity and behavioral abnormalities associated with neurodevelopmental disorders (NDDs). However, how microglial maturation and functions are regulated during early postnatal development remains poorly understood. Here, we investigated the role of serotonin (5-HT), for which microglia express specific receptors, in the regulation of microglial development and function during the early postnatal period. Using two complementary mouse models of altered serotonergic signaling : microglia-specific deletion of the 5-HT_2B receptor and postnatal exposure to the selective serotonin reuptake inhibitor fluoxetine, we performed bulk RNA sequencing of forebrain microglia at postnatal day 15. Transcriptomic analyses revealed that fluoxetine upregulated genes related notably to innate immunity and phagocytosis, while down-regulating genes associated with extracellular matrix organisation. Consistently, these functions were regulated in opposite ways in the microglia-specific knockout model. Noteworthy, fluoxetine-induced transcriptomic changes were more pronounced in females, revealing a sex-dependent microglial response to early-life serotonergic modulation. Comparison with published microglial developmental datasets further showed that microglia from fluoxetine-treated animals display a more mature transcriptomic profile. In addition, differentially expressed genes were significantly enriched for human autism spectrum disorder and other NDD risk gene sets. Together, these results identify serotonin as a key regulator of microglial maturation during postnatal brain development and suggest that altered serotonergic signaling may impact neurodevelopment through sex-dependent effects on microglia.