Neonatal inflammation disrupts a temporally restricted postnatal Numb-enriched microglial state in mice

Abstract

Early-life microglia are diverse and support brain development beyond immune surveillance, but the transient states associated with postnatal maturation remain poorly understood. Here we show, using a time-resolved single-cell atlas of neonatal mouse brain immune cells, that a postnatal Numb-enriched microglial state emerges during early postnatal development, expands during the second postnatal week and subsequently declines. This state is characterized by neurodevelopment-related gene expression programs and distinct metabolic features. Trajectory inference, cross-atlas mapping and RNAscope validation support its temporal pattern. During the period when this state expands, microglial depletion preserves gross myelination but alters synaptic protein composition and disrupts dendritic and cortical layer maturation, particularly in the primary somatosensory cortex. Neonatal lipopolysaccharide challenge impairs the establishment of the Numb-enriched state and induces an early glycolytic response followed by recovery-phase inflammatory states. These findings identify a developmentally timed microglial state associated with cortical maturation and vulnerable to neonatal inflammation in mice. Microglia help shape the developing brain, but how their early-life states change over time remains unclear. Here, the authors show that a transient Numb-enriched state marks postnatal cortical maturation in mice and is disrupted by neonatal inflammation.