ELUCIDATION OF THE INVOLVEMENT OF ASTROCYTE FUNCTION IN THE PATHOGENESIS OF GLUT1 DEFICIENCY SYNDROME

Abstract Background Glucose is a main energy source to support healthy brain function. Glucose transporter-1 (GLUT1) is the most important transport protein that transports glucose from the blood to the brain parenchyma and is reported to be expressed mainly in vascular endothelial cells and astrocyte endfeet. GLUT1 deficiency syndrome (GLUT1-DS) is a metabolic encephalopathy caused by impaired glucose transport into the brain. GLUT1-DS is a congenital disorder and heterozygous de novo mutations in the GLUT1 gene (SLC2A1) have been found in the majority of patients with GLUT1-DS, hypoglycaemia within the central nervous system, resulting in a range of CNS dysfunctions, including cognitive and motor dysfunction. Several papers have reported that Glut1 expressed in vascular endothelial cells (ECs) is important in neurological symptoms, and Adeno-associated virus (AAV)-based GLUT1 replacement therapy targeting vascular ECs is under development. Methods Astrocyte- and vascular EC-specific and systemic Glut1 haploinsufficient mice were used to attempt to identify the cells involved in the development of GLUT1-DS symptoms. Specifically, Aldh1l1-cre; Glut1 fl/+ mice were selected to analyze the contribution of astrocytes to GLUT1-DS symptoms and Tie2-cre; Glut1 fl/+ mice to analyze the contribution of ECs. Each mouse strain was used to measure glucose concentrations in cerebrospinal fluid (CSF) and interstitial fluid (ISF). These mice were also used in behavioral tests to assess cognitive and motor function, followed by evaluation of inflammation in the brain. Results First, Glut1 was found to be expressed throughout the astrocytic branches, not only in the endfeet. Next, compared to wild-type mice, all Glut1-deficient mouse strains showed reduced glucose levels in both CSF and ISF in addition to reduced cognitive and motor function. (All Glut1-deficient mouse strains: Aldh1l1-cre; Glut1 fl/+ mice, Tie2-cre; Glut1 fl/+ mice, Glut1 haploinsafficient mice). Conclusion These results suggest that Glut1 in astrocytes plays an important role in glucose uptake into CSF and ISF and in cognitive and motor functions. The two facts that Glut1 is expressed throughout astrocytes and the glucose concentration in ISF as well as CSF was reduced in Aldh1l1-cre; Glut1 fl/+ mice suggests that astrocytes may play a role in actively transporting glucose from blood to ISF. From this study, in addition to vascular ECs, GLUT1 in astrocytes is implicated in the pathogenesis of GLUT1-DS, suggesting that astrocytes may be a promising therapeutic target for GLUT1-DS.