Abstract
Glucose transporter type 1 deficiency syndrome (Glut1DS), also called De Vivo disease, is caused by mutations in SLC2A1gene that encodes for glucose transporter type 1 (Glut1). In the brain, Glut1 is predominantly expressed in endothelial cells of the blood brain barrier and astrocyte membranes. In humans, this mutation results in deficient glucose transport to the brain and is characterized by early onset epilepsy, complex movement disorders and cognitive impairment. In order to assess the impact of Glut1 deficiency on brain energy metabolism, we measured glycogen, lactate, and glucose levels in the cerebral cortex and hippocampus of a mouse model for Glut1DS. Glut1DS mice were obtained from the De Vivo laboratory and generated by targeted disruption of the mouse GLUT1 gene. GLUT1+/-mice mimic the major features of the classical phenotype of human Glut1DS (Wang D. et al, 2006). GLUT1+/-and wild type (WT) mice were sacrificed by focused microwave irradiation of the brain. Glycogen, lactate, and glucose levels were measured in the cerebral cortex and hippocampus using standard biochemical assays. A significant decrease in glucose levels was already observed at 2 weeks of age both in the hippocampus and the cerebral cortex of GLUT1 +/-mice compared to WT mice (-29% and -42%, respectively). In addition to decreased glucose, we found a significant reduction in glycogen concentrations (hippocampus: -29.8%, cerebral cortex: -30.9%) and lactate level (hippocampus: -36.9%, cerebral cortex: -24.7%). In 10-week-old mice, a similar decrease in glucose levels was observed in the hippocampus and cerebral cortex of GLUT1 +/-compared to WT mice (-31.9% and -40.8%, respectively). Decreases in glucose levels are accompanied by a significant reduction in cerebral glycogen content (hippocampus: -32.9%, cerebral cortex: -35.3%) and lactate levels (hippocampus: -15.7%, cerebral cortex: -17.8%) in GLUT1 +/-mice compared to WT mice. No difference in glycaemia and lactatemia was observed between GLUT1+/-and WT mice. In addition, there was no significant difference in glycogen, glucose and lactate levels between male and female in GLUT1+/-and WT mice. Together, these data show that Glut1DS has an early impact on brain energy metabolism not only on glucose levels but also on other important energy substrates including lactate and glycogen. As astrocytes store glycogen and release lactate, an important energy substrate and signaling molecule for neurons, these data suggest that Glut1DS may affect the metabolic cooperation between astrocytes and neurons. Further elucidation of the mechanisms underlying alterations in the astrocyte-neuron metabolic cooperation in GLUT1+/-mice should help to identify novel therapeutic targets for the treatment of De Vivo disease.