Astroglial Hmgb1 regulates postnatal astrocyte morphogenesis and cerebrovascular maturation

Astrocytes are intimately linked with brain blood vessels, a relationship critical for neuronal function. However, astroglial factors driving these physical and functional associations during postnatal brain development have yet to be identified. By characterizing structural and transcriptional changes in mouse cortical astrocytes during the first two postnatal weeks, we find that high-mobility group box 1 (Hmgb1), normally upregulated with injury and involved in adult cerebrovascular repair, is highly expressed in astrocytes at birth and then decreases rapidly. Astrocyte-selective ablation of Hmgb1 at birth affects astrocyte morphology and endfoot placement, alters distribution of endfoot proteins connexin43 and aquaporin-4, induces transcriptional changes in astrocytes related to cytoskeleton remodeling, and profoundly disrupts endothelial ultrastructure. While lack of astroglial Hmgb1 does not affect the blood-brain barrier or angiogenesis postnatally, it impairs neurovascular coupling and behavior in adult mice. These findings identify astroglial Hmgb1 as a key player in postnatal gliovascular maturation. We performed spatial gene expression profiling of astrocytes and microvessels on tissue sections from the developing postnatal mouse cerebral cortex, using the NanoString platform. Three postnatal time points were chosen (P0, P5 and P14) for comparisons. Only wild-type mice were used.