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

Metabolism. 2021 Mar:116:154463. doi: 10.1016/j.metabol.2020.154463. Epub 2020 Dec 10.

Abstract

Objectives: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Aerobic glycolysis; Astrocytes; GDI1 knockout mice; Intellectual disability; cAMP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Cells, Cultured
  • Deoxyglucose / pharmacology*
  • Deoxyglucose / therapeutic use
  • Down-Regulation / drug effects
  • Glucose / metabolism
  • Glycolysis / drug effects*
  • Guanine Nucleotide Dissociation Inhibitors / deficiency
  • Guanine Nucleotide Dissociation Inhibitors / genetics*
  • Intellectual Disability / drug therapy
  • Intellectual Disability / genetics*
  • Intellectual Disability / metabolism
  • Intellectual Disability / pathology
  • Male
  • Maze Learning / drug effects
  • Memory / drug effects
  • Memory Disorders / genetics
  • Memory Disorders / prevention & control*
  • Mice
  • Mice, Knockout

Substances

  • GDP dissociation inhibitor 1
  • Guanine Nucleotide Dissociation Inhibitors
  • Deoxyglucose
  • Glucose