Neuronal Activity–Dependent Metabolic Switch Drives Cerebrovascular Maturation in the Developing Visual Cortex

초록

Reciprocal signaling between neurons and vascular cells is essential for brain development and function. Neuronal activity regulates angiogenesis, hemodynamics, and blood–brain barrier (BBB) integrity by directly influencing brain endothelial cells (BECs) or indirectly via astrocytes and pericytes. In this study, we investigated how neuronal activation affects cerebrovascular maturation. Using translatome analysis of BECs at postnatal day 10 (P10, before eye-opening) and postnatal day 30 (P30, after eye-opening), we identified 30 light-responsive genes, including metabolite transporters GLUT1 (glucose transporter) and MCT1 (lactate transporter), which showed opposite temporal expression patterns: GLUT1 increased, while MCT1 decreased over time. Bioinformatic analysis revealed transforming growth factor-beta (TGF-β) signaling as a key upstream regulator. In cultured BECs, inhibition of TGF-β signaling modulated the expression of both transporters, whereas TGF-β ligand specifically increased MCT1 levels. Moverover, lactate treatment upregulated TGF-β1 expression, while MCT1 inhibition reduced it, indicating a positive feedback loop between lactate uptake and TGF-β signaling. Activation of TGF-β signaling induced BBB breakdown, associated with decreased expression of tight junction proteins ZO-1 and Claudin-5. Additionally, abnormal MCT1 expression impaired BBB maturation. Together, these findings demonstrate that a neuronal activity-driven, TGF-β–dependent shift in metabolite transporter expression is critical for cerebrovascular development and proper BBB formation during postnatal brain maturation.