Neurons require glucose uptake and glycolysis in vivo, 2023, Huihui Li et al

Highlights

• Neurons take up glucose and metabolize it by glycolysis to supply TCA metabolites
• HP 13C MRS shows disrupted brain energy when neuronal glucose metabolism is disrupted
• Mice require neuronal glucose uptake and glycolysis for learning and memory
• Galactose metabolism is upregulated to compensate for disrupted glucose metabolism

In brief Whether neurons can and must take up glucose and metabolize it by glycolysis was unclear, especially in vivo. Li et al. combine metabolomics and live imaging of human neurons with mouse models disrupting key steps in glucose metabolism to demonstrate that neurons require glucose uptake and glycolysis for normal function.

Summary
Neurons require large amounts of energy, but whether they can perform glycolysis or require glycolysis to maintain energy remains unclear.

Using metabolomics, we show that human neurons do metabolize glucose through glycolysis and can rely on glycolysis to supply tricarboxylic acid (TCA) cycle metabolites.

To investigate the requirement for glycolysis, we generated mice with postnatal deletion of either the dominant neuronal glucose transporter (GLUT3cKO) or the neuronal-enriched pyruvate kinase isoform (PKM1cKO) in CA1 and other hippocampal neurons. GLUT3cKO and PKM1cKO mice show age-dependent learning and memory deficits. Hyperpolarized magnetic resonance spectroscopic (MRS) imaging shows that female PKM1cKO mice have increased pyruvate-to-lactate conversion, whereas female GLUT3cKO mice have decreased conversion, body weight, and brain volume. GLUT3KO neurons also have decreased cytosolic glucose and ATP at nerve terminals, with spatial genomics and metabolomics revealing compensatory changes in mitochondrial bioenergetics and galactose metabolism.

Therefore, neurons metabolize glucose through glycolysis in vivo and require glycolysis for normal function.

https://www.cell.com/cell-reports/pdf/S2211-1247(23)00346-7.pdf