@article{10.1172/jci.insight.145789, author = {Maoxue Tang AND Sarah H. Park AND Sabrina Petri AND Hang Yu AND Carlos B. Rueda AND E. Dale Abel AND Carla Y. Kim AND Elizabeth M.C. Hillman AND Fanghua Li AND Yeojin Lee AND Lei Ding AND Smitha Jagadish AND Wayne N. Frankel AND Darryl C. De Vivo AND Umrao R. Monani}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {An early endothelial cell–specific requirement for Glut1 is revealed in Glut1 deficiency syndrome model mice}, year = {2021}, month = {2}, volume = {6}, url = {https://insight.jci.org/articles/view/145789}, abstract = {Paucity of the glucose transporter-1 (Glut1) protein resulting from haploinsufficiency of the SLC2A1 gene arrests cerebral angiogenesis and disrupts brain function to cause Glut1 deficiency syndrome (Glut1 DS). Restoring Glut1 to Glut1 DS model mice prevents disease, but the precise cellular sites of action of the transporter, its temporal requirements, and the mechanisms linking scarcity of the protein to brain cell dysfunction remain poorly understood. Here, we show that Glut1 functions in a cell-autonomous manner in the cerebral microvasculature to affect endothelial tip cells and, thus, brain angiogenesis. Moreover, brain endothelial cell–specific Glut1 depletion not only triggers a severe neuroinflammatory response in the Glut1 DS brain, but also reduces levels of brain-derived neurotrophic factor (BDNF) and causes overt disease. Reduced BDNF correlated with fewer neurons in the Glut1 DS brain. Controlled depletion of the protein demonstrated that brain pathology and disease severity was greatest when Glut1 scarcity was induced neonatally, during brain angiogenesis. Reducing Glut1 at later stages had mild or little effect. Our results suggest that targeting brain endothelial cells during early development is important to ensure proper brain angiogenesis, prevent neuroinflammation, maintain BDNF levels, and preserve neuron numbers. This requirement will be essential for any disease-modifying therapeutic strategy for Glut1 DS.}, number = {3}, doi = {10.1172/jci.insight.145789}, url = {https://doi.org/10.1172/jci.insight.145789}, }