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.
Highlights
Heterozygous mutations in the SLC2A1 gene and reduced levels of its translated product, the glucose transporter-1 (Glut1) protein, elicit neuroglycopenia in what is known as Glut1 deficiency syndrome (Glut1 DS; ref. 1)
Systemic Glut1 haploinsufficiency results in fewer brain capillaries and triggers Glut1 DS [12]. To determine if this is a cell-autonomous effect of Glut1 in endothelial cells (ECs), we selectively depleted the transporter in these cells
Depleting the transporter in ECs resulted in, more or less, the entire gamut of cellular and behavioral phenotypes associated with the human condition, but it revealed potentially novel defects in a select population of these cells — tip cells, which are crucial for brain angiogenesis
Summary
Heterozygous mutations in the SLC2A1 gene and reduced levels of its translated product, the glucose transporter-1 (Glut1) protein, elicit neuroglycopenia in what is known as Glut deficiency syndrome (Glut DS; ref. 1). Heterozygous mutations in the SLC2A1 gene and reduced levels of its translated product, the glucose transporter-1 (Glut1) protein, elicit neuroglycopenia in what is known as Glut deficiency syndrome The expanded phenotype, combined with reports that SLC2A1 mutations account for approximately 1% of idiopathic generalized epilepsies [5] and approximately 10% of absence epilepsies [6], suggests that the disease is more prevalent than originally thought; it is estimated that there are at least 4500 Glut DS patients in the US alone [7]. The molecular cause of Glut DS was described more than 2 decades ago, there is still no truly effective disease-modifying treatment for the disorder. While the diet does mitigate seizure activity, it does not have a measurable effect on other disease symptoms [11]
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