The Role of Astrocyte-Neuron Interactions in Shaping Neuronal Maturation during Human Brain Development

The human brain undergoes extensive transcriptomic remodeling during the perinatal period and early postnatal development, yet the cellular basis and regulatory logic underlying these changes remain unclear. By integrating single-cell and bulk RNA sequencing data across 9 developmental stages of the human cerebral cortex, we systematically characterized the temporal dynamics of gene expression across major cell types. From late fetal stages to infancy, pronounced transcriptomic changes occur, accompanied by shifts in cellular composition and gene expression programs. During this period, glial cells exhibit gene expression patterns and computationally inferred signaling features consistent with ongoing neuronal maturation. Cell-cell communication analysis further suggests that astrocyte subtypes exhibit distinct interaction patterns with neurons, characterized by subtype-specific temporal dynamics and lineage-associated features. Comparative analyses with mouse brains reveal human-specific features in synaptogenesis and axonogenesis that coincide with the evolutionary divergence of astrocyte subtypes. In addition, immature and mature astrocyte subtypes show distinct associations with neuronal maturation, and their developmental transitions align with stages of increased transcriptomic divergence. These findings provide new insights into how astrocyte subtypes in the postnatal human brain may contribute to neuronal development and circuit formation during critical developmental periods, and offer clues to the potential origins of neurodevelopmental disorders.