Inhibiting glycolysis rescues memory impairment in an intellectual disability Gdi1-null mouse.

GDI1 gene encodes for αGDI, a protein controlling the cycling of small GTPases, reputed to orchestrate vesicle trafficking. Mutations in human GDI1 are responsible for intellectual disability (ID). In mice with ablated Gdi1, a model of ID, impaired working and associative short-term memory was recorded. This cognitive phenotype worsens if the deletion of αGDI expression is restricted to neurons. However, whether astrocytes, key homeostasis providing neuroglial cells, supporting neurons via aerobic glycolysis, contribute to this cognitive impairment is unclear. We carried out proteomic analysis and monitored [18F]-fluoro-2-deoxy-d-glucose uptake into brain slices of Gdi1 knockout and wild type control mice. d-Glucose utilization at single astrocyte level was measured by the Förster Resonance Energy Transfer (FRET)-based measurements of cytosolic cyclic AMP, d-glucose and L-lactate, evoked by agonists selective for noradrenaline and L-lactate receptors. To test the role of astrocyte-resident processes in disease phenotype, we generated an inducible Gdi1 knockout mouse carrying the Gdi1 deletion only in adult astrocytes and conducted behavioural tests. Proteomic analysis revealed significant changes in astrocyte-resident glycolytic enzymes. Imaging [18F]-fluoro-2-deoxy-d-glucose revealed an increased d-glucose uptake in Gdi1 knockout tissue versus wild type control mice, consistent with the facilitated d-glucose uptake determined by FRET measurements. In mice with Gdi1 deletion restricted to astrocytes, a selective and significant impairment in working memory was recorded, which was rescued by inhibiting glycolysis by 2-deoxy-d-glucose injection. These results reveal a new astrocyte-based mechanism in neurodevelopmental disorders and open a novel therapeutic opportunity of targeting aerobic glycolysis, advocating a change in clinical practice. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Patrizia D'Adamo, Anemari Horvat, Antonia Gurgone, Maria Lidia Mignogna, Veronica Bianchi, Michela Masetti, Maddalena Ripamonti, Stefano Taverna, Jelena Velebit, Maja Malnar, Marko Muhič, Katja Fink, Angela Bachi, Umberto Restuccia, Sara Belloli, Rosa Maria Moresco, Alessia Mercalli, Lorenzo Piemonti, Maja Potokar, Saša Trkov Bobnar, Marko Kreft, Helena H Chowdhury, Matjaž Stenovec, Nina Vardjan, Robert Zorec. Inhibiting glycolysis rescues memory impairment in an intellectual disability Gdi1-null mouse. Metabolism: clinical and experimental. 2021 Mar;116:154463

Mesh Tags

Substances

PMID: 33309713

search → result