Impact of GLUT1 transporter knockout in optic nerve head astrocytes and retinal ganglion cells




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Introduction: Astrocytes and RGC axons are the primary constituents of the optic nerve head, the initial site of neurodegeneration in glaucoma. This study was intended to understand the metabolic relationship between them. We hypothesized that reducing glucose transporter-1 (GLUT1) expression in astrocytes will increase the RGC-associated pathology after ocular hypertension (OHT). Methods: Mice carrying a GLUT1 gene flanked by loxP sites crossed with a mouse carrying the glial fibrillary acidic protein (GFAP) promoter directing a Cre-ERT2 fusion protein (GFAP-GLUT1") were used (n=30) and were divided into 4 groups: GLUT1-knockout+OHT (Tamox OHT), Control OHT, GLUT1-knockout+No OHT (Tamox), and Control+No OHT (Control naïve). Baseline and final intra-ocular pressure (IOP), pattern electroretinogram (PERG), and visual evoked potential (VEP) measurements were taken. OHT was induced via magnetic microbead injection. Retinas, optic nerves, and brains were collected for retinal ganglion cell (RGC) quantification, synapse analysis, biochemical assays, and protein analysis. Results: Statistically significant increases were noted in the IOP data between mice subjected to OHT and the No OHT groups. OHT led to statistically significant decreases in RGC number, regardless of GLUT1 status. Statistically significant decreases in PERG amplitude were noted in all groups subjected to OHT. GLUT1 knockout PERG amplitude was significantly lower than Control at the outset, suggesting a negative impact on retinal physiology from loss of the GLUT1 in astrocytes. Conclusion: Our data indicate glial metabolic homeostasis can impact retinal physiology, but GLUT1 knockout did not appear, on its own, to negatively impact RGC survival. Future studies will give us better understanding of other structural or functional compromise induced by loss of GLUT1 in astrocytes, including potential compensatory mechanisms that enabled astrocytes to meet their metabolic needs.