Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism

• Published in: Neuron (Cambridge, Mass.) Mass.), 2016-07, Vol.91 (1), p.119-132
• Main Authors: Saab, Aiman S., Tzvetavona, Iva D., Trevisiol, Andrea, Baltan, Selva, Dibaj, Payam, Kusch, Kathrin, Möbius, Wiebke, Goetze, Bianka, Jahn, Hannah M., Huang, Wenhui, Steffens, Heinz, Schomburg, Eike D., Pérez-Samartín, Alberto, Pérez-Cerdá, Fernando, Bakhtiari, Davood, Matute, Carlos, Löwel, Siegrid, Griesinger, Christian, Hirrlinger, Johannes, Kirchhoff, Frank, Nave, Klaus-Armin
• Format: Article
• Language: English
• Subjects: Animals; Axons - metabolism; Binding sites; Energy Metabolism - physiology; Experiments; Glucose; Glucose - metabolism; Glucose Transporter Type 1 - metabolism; Metabolism; Metabolites; Mice, Transgenic; Microscopy; Myelin Sheath - metabolism; Oligodendroglia - metabolism; Optic nerve; Optic Nerve - metabolism; Oxygen - metabolism; Proteins; Receptors, N-Methyl-D-Aspartate - metabolism; Rodents; Sensors
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2016.05.016

Oligodendrocytes make myelin and support axons metabolically with lactate. However, it is unknown how glucose utilization and glycolysis are adapted to the different axonal energy demands. Spiking axons release glutamate and oligodendrocytes express NMDA receptors of unknown function. Here we show that the stimulation of oligodendroglial NMDA receptors mobilizes glucose transporter GLUT1, leading to its incorporation into the myelin compartment in vivo. When myelinated optic nerves from conditional NMDA receptor mutants are challenged with transient oxygen-glucose deprivation, they show a reduced functional recovery when returned to oxygen-glucose but are indistinguishable from wild-type when provided with oxygen-lactate. Moreover, the functional integrity of isolated optic nerves, which are electrically silent, is extended by preincubation with NMDA, mimicking axonal activity, and shortened by NMDA receptor blockers. This reveals a novel aspect of neuronal energy metabolism in which activity-dependent glutamate release enhances oligodendroglial glucose uptake and glycolytic support of fast spiking axons. •Oligodendroglial NMDA receptors regulate GLUT1 trafficking and glucose import•Mouse mutants lacking NMDA receptors from oligodendrocytes are delayed in myelination•Activation of oligodendroglial NMDA receptor supports the axonal energy metabolism•Mice lacking oligodendroglial NMDA receptors develop late-onset axonopathy and neuroinflammation Saab et al. identify a novel feature of axonal metabolic support. Activation of oligodendroglial NMDA receptors stimulates GLUT1 export and release of lactate. Targeted inactivation of oligodendroglial NMDA receptors in vivo impairs axonal energy metabolism and causes late-onset axonopathy.