Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism.
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.
Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Göttingen 37075, Germany; Center for Integrative Physiology and Molecular Medicine, Molecular Physiology, University of Saarland, Homburg 66421, Germany; University of Zurich, Institute of Pharmacology and Toxicology, 8057 Zurich, Switzerland.
Aiman S
AS
Saab
Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Göttingen 37075, Germany.
Iva D
ID
Tzvetavona
Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Göttingen 37075, Germany.
Andrea
A
Trevisiol
Lerner Research Institute, Cleveland Clinic, Department of Neurosciences, Cleveland, OH 44195, USA.
Selva
S
Baltan
Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Göttingen 37075, Germany.
Payam
P
Dibaj
Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Göttingen 37075, Germany.
Kathrin
K
Kusch
Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Göttingen 37075, Germany; Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), 37073 Göttingen, Germany.
Wiebke
W
Möbius
Bernstein Focus for Neurotechnology (BFNT) and School of Biology, Department of Systems Neuroscience, University of Göttingen, 37075 Göttingen, Germany.
Bianka
B
Goetze
Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Göttingen 37075, Germany; Center for Integrative Physiology and Molecular Medicine, Molecular Physiology, University of Saarland, Homburg 66421, Germany.
Hannah M
HM
Jahn
Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Göttingen 37075, Germany; Center for Integrative Physiology and Molecular Medicine, Molecular Physiology, University of Saarland, Homburg 66421, Germany.
Wenhui
W
Huang
Institute of Physiology, University of Göttingen, 37073 Göttingen, Germany; Max Planck Institute for Biophysical Chemistry, Department of NanoBiophotonics, 37077 Göttingen, Germany.
Heinz
H
Steffens
Institute of Physiology, University of Göttingen, 37073 Göttingen, Germany.
Eike D
ED
Schomburg
Universidad del País Vasco, CIBERNED and Departamento de Neurociencias and Achucarro Basque Center for Neuroscience, Leioa 48940, Spain.
Alberto
A
Pérez-Samartín
Universidad del País Vasco, CIBERNED and Departamento de Neurociencias and Achucarro Basque Center for Neuroscience, Leioa 48940, Spain.
Fernando
F
Pérez-Cerdá
Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), 37073 Göttingen, Germany; Department of NMR Based Structural Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
Davood
D
Bakhtiari
Universidad del País Vasco, CIBERNED and Departamento de Neurociencias and Achucarro Basque Center for Neuroscience, Leioa 48940, Spain.
Carlos
C
Matute
Bernstein Focus for Neurotechnology (BFNT) and School of Biology, Department of Systems Neuroscience, University of Göttingen, 37075 Göttingen, Germany.
Siegrid
S
Löwel
Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), 37073 Göttingen, Germany; Department of NMR Based Structural Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
Christian
C
Griesinger
Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Göttingen 37075, Germany; Carl-Ludwig-Institute for Physiology, Faculty of Medicine, University of Leipzig, 04103 Leipzig, Germany.
Johannes
J
Hirrlinger
Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Göttingen 37075, Germany; Center for Integrative Physiology and Molecular Medicine, Molecular Physiology, University of Saarland, Homburg 66421, Germany; Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), 37073 Göttingen, Germany. Electronic address: frank.kirchhoff@uks.eu.
Frank
F
Kirchhoff
Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Göttingen 37075, Germany; Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), 37073 Göttingen, Germany. Electronic address: nave@em.mpg.de.
Klaus-Armin
KA
Nave
D000818:Animals; D001369:Axons / Q000378:metabolism*; D004734:Energy Metabolism / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism*; D009900:Optic Nerve / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
D051272:Glucose Transporter Type 1; D016194:Receptors, N-Methyl-D-Aspartate; C495678:Slc2a1 protein, mouse; D005947:Glucose; D010100:Oxygen