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Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism
Open accessAbstract
SUMMARY 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.
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TL;DR
Oligodendroglial NMDA receptor activation mobilizes GLUT1 to the cell surface/myelin and increases glucose import and lactate release, coupling axonal spiking to oligodendroglial glycolytic support. Conditional NR1 loss reduces myelin GLUT1, impairs recovery from oxygen-glucose deprivation unless lactate is supplied, and causes late axonal and neurological deficits.
Key findings
- In cultured oligodendrocytes, NMDA triggered GLUT1 surface redistribution within 30 min, blocked by D-AP5; biotinylation showed a 2-fold surface GLUT1 increase, FRET glucose sensor measurements rose from 0.56 ± 0.04 mM at baseline to 1.85 ± 0.24 mM after NMDA, and NMR showed a 24% ± 4% increase in U-13C-lactate release; MCT1 was unchanged.
- In Grin1flox/flox*Cnp1Cre/+ (NR1 cKO) optic nerves, myelin GLUT1 was reduced by 80%, recombination reached 62% ± 8% at P96, and myelin was transiently thinner at P18–P20 but normal at P70.
- After 60-min oxygen-glucose deprivation, NR1 mutant optic nerves recovered 50% less than controls; lactate reperfusion restored recovery equal to or better than glucose; wild-type nerves preincubated 16 hr with NMDA/Gly maintained high-frequency conduction better, while D-AP5/7CKA worsened it, and without NMDA, 25 Hz stimulation caused about 10% decline per min.
- Adult NR1 mutants showed faster high-frequency spinal CAP amplitude drop and slower recovery, a 1-year rotarod deficit, and at 19 months a severe neurological phenotype including hind limb clasping, hunchback, and ataxia with neuroinflammation and axonopathy in white matter tracts.
Methods
- Conditional NR1 knockout mice (Grin1flox/flox*Cnp1Cre/+) versus controls, plus primary mouse/rat OPC cultures and immunopanned oligodendrocytes; assays included immunocytochemistry, surface biotinylation, FRET glucose sensor imaging, 2-deoxyglucose uptake, NMR lactate release, myelin purification/immunoblot, immunogold EM, optic nerve CAP recordings with OGD and graded frequency, in vivo spinal cord CAP recordings, rotarod, and clinical scoring.
- Statistics used Mann-Whitney, two-tailed Student’s t tests, one-way or two-way ANOVA with Bonferroni post-test, or linear mixed effects models; significance was set at *p < 0.05, p < 0.01, *p < 0.001, with data as means ± SEM.
Limitations
- Stated: astrocytes may compensate some metabolic functions in oligodendroglial NMDA receptor mutants; acute ex vivo NMDA receptor blockade did not visibly reduce recovery from OGD, which the authors attribute to different timescales between development and pharmacology; some mechanistic data (insulin mobilization, microtubule dependence) are “data not shown.”
- Evident: findings rely on rodent optic nerve/spinal cord and cultured oligodendrocytes; axonal energy metabolism is inferred from conduction recovery and lactate rescue rather than direct ATP measurement; no human data are presented.
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53 Own result · 13 Own interpretation · 11 Not checked yet · 5 Own method · 2 No basis given
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“that was efficiently blocked by D-(−)-2-amino-5-phosphonopentanoic acid (D-AP5)”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > NMDA Receptor Activation Triggers GLUT1 Surface Expression and Enhances Glucose Import in Cultured Oligodendrocytes
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“Activation of NMDA receptors caused a significantly increased FRET signal”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > NMDA Receptor Activation Triggers GLUT1 Surface Expression and Enhances Glucose Import in Cultured Oligodendrocytes
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“whereas the abundance of MCT1 was the same”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > NMDA Receptor Activation Triggers GLUT1 Surface Expression and Enhances Glucose Import in Cultured Oligodendrocytes
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“we calculated a 24% ± 4% increase of U-13C-lactate release originating from U-13C6-labeled glucose”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > NMDA Receptor Activation Triggers GLUT1 Surface Expression and Enhances Glucose Import in Cultured Oligodendrocytes
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“that was abolished by 7-CKA and D-AP5”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > NMDA Receptor Activation Triggers GLUT1 Surface Expression and Enhances Glucose Import in Cultured Oligodendrocytes
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“revealing a 2-fold GLUT1 increase at the cell surface following 30 min NMDA stimulation”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > NMDA Receptor Activation Triggers GLUT1 Surface Expression and Enhances Glucose Import in Cultured Oligodendrocytes
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“quantified the uptake of 2-deoxyglucose (2DG) to confirm that NMDA elevates glucose import”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > NMDA Receptor Activation Triggers GLUT1 Surface Expression and Enhances Glucose Import in Cultured Oligodendrocytes
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“there were no signs of oligodendrocyte death”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > NMDA Receptor Activation Triggers GLUT1 Surface Expression and Enhances Glucose Import in Cultured Oligodendrocytes
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“In contrast, monocarboxylate transporter MCT1 distribution was unaffected by NMDA”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > NMDA Receptor Activation Triggers GLUT1 Surface Expression and Enhances Glucose Import in Cultured Oligodendrocytes
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“NR1 was lost by immunostaining, as shown for optic nerve”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > Myelination In Vivo in the Absence of Oligodendroglial NMDA Receptors
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“i.e., 0.56 ± 0.04 mM at baseline and 1.85 ± 0.24 mM following NMDA receptor stimulation”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > NMDA Receptor Activation Triggers GLUT1 Surface Expression and Enhances Glucose Import in Cultured Oligodendrocytes
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“Remarkably, treatment with NMDA triggered GLUT1 redistribution in oligodendrocytes within 30 min, leading to apparent surface expression”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > NMDA Receptor Activation Triggers GLUT1 Surface Expression and Enhances Glucose Import in Cultured Oligodendrocytes
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“at P10, when many oligodendrocytes had matured and express Cnp1, about one-third of the floxed alleles were excised, and recombination reached 62% ± 8% at P96”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > Myelination In Vivo in the Absence of Oligodendroglial NMDA Receptors
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“At the age of 19 months, NR1 mutants exhibited a severe neurological phenotype including hind limb clasping, hunchback, and ataxia”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > In Vivo Relevance of Oligodendroglial NMDA Receptor Function
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“While most white and gray matter regions in mutant mice, including optic nerves, appeared devoid of pathology within the first year (data not shown), such changes became detectable in white matter tracts of the medulla”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > In Vivo Relevance of Oligodendroglial NMDA Receptor Function
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“we observed myelin delamination and degenerating axons in cervical spinal cord sections”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > In Vivo Relevance of Oligodendroglial NMDA Receptor Function
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“We detected no overt differences between NR1 mutants and controls in spinal conduction properties or axon excitability”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > In Vivo Relevance of Oligodendroglial NMDA Receptor Function
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“we found no difference in the onset of EAE symptoms or in clinical severity”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > Causality of NMDA Receptor Signaling and Glucose Metabolism in Axonal Support
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“we noted at ages P18–P20 that myelin was thinner, with fewer myelinated axons in the mutant optic nerves”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > Myelination In Vivo in the Absence of Oligodendroglial NMDA Receptors
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“all optic nerves maintained conductivity (defined as “CAP area” of 1.0) and, within minutes after OGD onset, displayed block of nerve conduction”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > Functional Analysis of Myelinated Axons
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“This difference was only transient as adult (P70) NR1 mutant optic nerves “catch up” and exhibit a normal myelin sheath thickness”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > Myelination In Vivo in the Absence of Oligodendroglial NMDA Receptors
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“in the absence of free extracellular Ca2+, the axonal recovery was almost 100% in control nerves yet remained significantly impaired in NR1 mutants”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > Causality of NMDA Receptor Signaling and Glucose Metabolism in Axonal Support
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“CAP profiles revealed a transiently reduced conduction velocity, again only at the peak of myelination (age P19–P21) and mainly affecting small caliber axons”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > Functional Analysis of Myelinated Axons
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“using lactate-containing ACSF for reperfusion, optic nerves from NR1 mutants recovered as well as control nerves and even better than in the presence of glucose”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > Causality of NMDA Receptor Signaling and Glucose Metabolism in Axonal Support
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“In purified myelin from mutant brains, we found a strong reduction of GLUT1 (but not MCT1) compared to controls”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > Myelination In Vivo in the Absence of Oligodendroglial NMDA Receptors
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“mutant mice were normally developed with functional white matter tracts, as shown for the optic nerve”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > Myelination In Vivo in the Absence of Oligodendroglial NMDA Receptors
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“when triggered with NMDA, trafficking was expectedly calcium dependent and required a stable microtubule network”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > DISCUSSION
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“Most likely, membrane repolarization (triggered by NMDA receptor signaling and ion influx) consumes the additional ATP and leads to more glycolysis with lactate release.”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > NMDA Receptor Activation Triggers GLUT1 Surface Expression and Enhances Glucose Import in Cultured Oligodendrocytes
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“Thus, further loss of axonal conductivity was not caused by more severe myelin injury, but rather by less-efficient axonal recovery from the metabolic stress of OGD.”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > Functional Analysis of Myelinated Axons
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In the paper
“In development, NMDA receptors are most abundant in oligodendrocyte precursors”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > DISCUSSION
What the sources say
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In the paper
“In myelin, NR1 is associated with NR2C and NR3A subunits that provide a weak Mg2+ block”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > DISCUSSION
What the sources say
- Not checked yetcites Burzomato et al., 2010 source
- Not checked yetcites Das et al., 1998
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“suggesting that axons require oligodendroglial support mostly after myelination, which limits rapid axonal access to extracellular metabolites”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > Functional Analysis of Myelinated Axons
What the sources say
- Not checked yetcites Nave, 2010 source
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“These are best explained by the delay of CNS myelination”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > Functional Analysis of Myelinated Axons
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“caused by ongoing neurodegeneration, which became visible at 10 months”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > RESULTS > In Vivo Relevance of Oligodendroglial NMDA Receptor Function
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In the paper
“For quantification, 10–12 randomly taken images from three controls and three NR1 mutants were assessed.”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > EXPERIMENTAL PROCEDURES > Immunoelectron Microscopy
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In the paper
“Oligodendroglial NMDA receptors are localized in specialized microdomains of myelinating processes”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > DISCUSSION
What the sources say
- Not checked yetcites Stirling and Stys, 2010
- Not checked yetcites Stys, 2011 source
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“They have direct access to the vasculature, store glycogen, and rapidly respond to energy deprivation with glycogen breakdown”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > DISCUSSION
What the sources say
- Not checked yetcites Brown and Ransom, 2007
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“For g-ratio analysis, 4–5 random overview pictures were taken at 8,000× magnification, 200 axons analyzed using ImageJ (images were blinded for experimenter).”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > EXPERIMENTAL PROCEDURES > Electron Microscopy and Morphometry
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“OPCs utilized for biotinylation assays, 2-deoxyglucose uptake, or lactate release were further purified to 98.2% ± 0.3% by negative selection immunopanning (Barres et al., 1992).”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > EXPERIMENTAL PROCEDURES > Cell Culture Preparation
What the sources say
- Not checked yetcites Barres et al., 1992 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For analysis of unmyelinated, myelinated, and ensheathed axons (defined as 1–3 uncompacted layers), 4–6 EM images with 12,000× magnification 400–700 axons were counted for each nerve.”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > EXPERIMENTAL PROCEDURES > Electron Microscopy and Morphometry
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“astrocytes can also support axon function by releasing lactate in the white matter”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > DISCUSSION
What the sources say
- Not checked yetcites Brown and Ransom, 2007
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Three individual experiments with 14–24 cells per condition were analyzed.”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > EXPERIMENTAL PROCEDURES > Immunocytochemistry
plainn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“After OGD control ACSF and O2 were restored and CAPs were recorded for up to 2–3 hr, responses were stabilized within 20 to 30 min.”
§ Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism > EXPERIMENTAL PROCEDURES > Optic Nerve Recordings
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
The average spike count rate is the key determinant of axonal ATP consumption.
“Since the average spike count rate is the key determinant of axonal ATP consumption”
The paper relies on this without support.
Constitutive overproduction of lactate would result in lactic acidosis detrimental for white matter function.
“The constitutive overproduction of lactate would result in lactic acidosis, detrimental for white matter function.”
The paper relies on this without support.
Oligodendrocytes need to know the spiking activity of myelinated axons to adapt their own energy metabolism.
“oligodendrocytes need to “know” the spiking activity of myelinated axons”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The model is further supported by ex vivo electrophysiological recordings of compound action potentials in optic nerves under defined metabolic conditions and with the help of neuronally expressed ATP sensors (Saab et al., 2016;Trevisiol et al., 2017).”
From Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons (2024) · cites this paper as Saab et al., 2016
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“that recombines floxed genes to virtually 100% in oligodendrocytes and up to 60% of OPCs (Madsen et al., 2016;Saab et al., 2016;Vajda et al., 2015).”
From Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons (2024) · cites this paper as Saab et al., 2016
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“we turned to the analysis of the optic nerve, a well-myelinated white matter tract, in which all Cnp Cre recombined cells are of oligodendroglial origin (Saab et al., 2016).”
From Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons (2024) · cites this paper as Saab et al., 2016
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“As oligodendrocytes support axonal energy metabolism and neuronal health4–7, we hypothesized that loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the central neuropathological hallmark of AD.”
From Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease (2023) · cites this paper as [7]
The cited source says what the claim attributes to it.
In the citing paper
“This opens the possibility that glycolytic oligodendrocytes, which are suggested to support electrically active axons with an excess of glycolysis products (Fünfschilling et al., 2012;Lee et al., 2012;Saab et al., 2016;Trevisiol et al., 2017) do so primarily by self-made pyruvate.”
From Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons (2024) · cites this paper as Saab et al., 2016
In the citing paper
“Either glucose or lactate can be used as an energy source for white matter (Brown et al., 2001; Saab et al., 2016),”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Saab et al., 2016
Citations
Cites
Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O'Keeffe, S., Phatnani, H. P., Guarnieri, P., Caneda, C., Ruderisch, N., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.1860-14.2014 · Cited by 4,875 · cited 7×
“GLUT1 mRNA is more abundant in mature oligodendrocytes than in precursor cells (Zhang et al., 2014).”
InfluentialPreparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue.
McCarthy, K. D., & de Vellis, J. (1980) · The Journal of Cell Biology · doi:10.1083/jcb.85.3.890 · Cited by 3,845
Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus
Srinivas, S., Watanabe, T., Lin, C.-S., William, C. M., Tanabe, Y., Jessell, T. M., & Costantini, F. (2001) · BMC Developmental Biology · doi:10.1186/1471-213x-1-4 · Cited by 3,121 · cited 1×
“Some of the mice also carried the R26-stop-EYFP reporter gene for Cre activity (RRID: IMSR_ JAX:006148) (Srinivas et al., 2001).”
The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory.
Tsien, J. Z., Huerta, P. T., & Tonegawa, S. (1996) · Cell · doi:10.1016/s0092-8674(00)81827-9 · Cited by 1,782 · cited 8×
“, 2003) were crossbred to floxed NR1 (gene symbol Grin1) mice (RRID: MGI_2175051) (Tsien et al., 1996).”
InfluentialOligodendroglia metabolically support axons and contribute to neurodegeneration
Lee, Y., Morrison, B. M., Li, Y., Lengacher, S., Farah, M. H., Hoffman, P. N., Liu, Y., Tsingalia, A., Jin, L., Zhang, P.-W., et al. (2012) · Nature · doi:10.1038/nature11314 · Cited by 1,664 · cited 5×
“This confirms that axons readily use lactate for ATP generation (Fünfschilling et al., 2012; Lee et al., 2012; Tekkök et al., 2005; Wyss et al., 2011).”
InfluentialGlycolytic oligodendrocytes maintain myelin and long-term axonal integrity
Fünfschilling, U., Supplie, L. M., Mahad, D., Boretius, S., Saab, A. S., Edgar, J., Brinkmann, B. G., Kassmann, C. M., Tzvetanova, I. D., Möbius, W., et al. (2012) · Nature · doi:10.1038/nature11007 · Cited by 1,523 · cited 5×
“This confirms that axons readily use lactate for ATP generation (Fünfschilling et al., 2012; Lee et al., 2012; Tekkök et al., 2005; Wyss et al., 2011).”
InfluentialSelf-citationNeuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain
Gibson, E. M., Purger, D., Mount, C. W., Goldstein, A. K., Lin, G. L., Wood, L. S., Inema, I., Miller, S. E., Bieri, G., Zuchero, J. B., et al. (2014) · Science · doi:10.1126/science.1252304 · Cited by 1,472 · cited 2×
“…signaling in oligodendrocyte differentiation and promoting myelinationhasbeensuggested, basedon in vitroobservations (Li et al., 2013; Lundgaard et al., 2013), which is compatible with neuronal activity stimulating OPC proliferation and myelination in vivo (Gibson et al., 2014; Liu et al., 2012).”
MYELINATION IN RAT BRAIN: METHOD OF MYELIN ISOLATION1
Norton, W. T., & Poduslo, S. E. (1973) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1973.tb07519.x · Cited by 1,413 · cited 2×
“Myelin was purified as described before (Norton and Poduslo, 1973) from mouse brain homogenate in 0.32 M sucrose.”
InfluentialCell death and control of cell survival in the oligodendrocyte lineage
Barres, B. A., Hart, I. K., Coles, H. S. R., Burne, J. F., Voyvodic, J. T., Richardson, W. D., & Raff, M. C. (1992) · Cell · doi:10.1016/0092-8674(92)90531-g · Cited by 1,345 · cited 2×
“3% by negative selection immunopanning (Barres et al., 1992).”
InfluentialDisruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination
Lappe-Siefke, C., Goebbels, S., Gravel, M., Nicksch, E., Lee, J., Braun, P. E., Griffiths, I. R., & Nave, K.-A. (2003) · Nature Genetics · doi:10.1038/ng1095 · Cited by 1,036 · cited 8×
“Oligodendroglial metabolic support can explain why myelinated axons are vitally dependent on myelin integrity, independent of the myelin function in saltatory conduction (Griffiths et al., 1998; Kassmann et al., 2007; Lappe-Siefke et al., 2003).”
InfluentialSelf-citation
Cited by
Sorted by citations
Lactate in the brain: from metabolic end-product to signalling molecule
Magistretti, P. J., & Allaman, I. (2018) · Nature Reviews Neuroscience · doi:10.1038/nrn.2018.19 · Cited by 1,298
Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing
Cunnane, S. C., Trushina, E., Morland, C., Prigione, A., Casadesus, G., Andrews, Z. B., Beal, M. F., Bergersen, L. H., Brinton, R. D., de la Monte, S., et al. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0072-x · Cited by 1,003
Self-citationNew Horizons in Diabetic Neuropathy: Mechanisms, Bioenergetics, and Pain
Feldman, E. L., Nave, K.-A., Jensen, T. S., & Bennett, D. L. H. (2017) · Neuron · doi:10.1016/j.neuron.2017.02.005 · Cited by 915
Self-citationMyelin in the Central Nervous System: Structure, Function, and Pathology
Stadelmann, C., Timmler, S., Barrantes‐Freer, A., & Simons, M. (2019) · Physiological Reviews · doi:10.1152/physrev.00031.2018 · Cited by 799
“Oligodendrocytes appear to sense the metabolic demands of axons by N-methyl-D-aspartate (NMDA) receptors that are associated with the internodal/paranodal membrane (538).”
BackgroundBrain Cell Type Specific Gene Expression and Co-expression Network Architectures
McKenzie, A. T., Wang, M., Hauberg, M. E., Fullard, J. F., Kozlenkov, A., Keenan, A., Hurd, Y. L., Dracheva, S., Casaccia, P., Roussos, P., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-27293-5 · Cited by 481
Metadata
- Authors
- Saab, A. S., Tzvetavona, I. D., Trevisiol, A., Baltan, S., Dibaj, P., Kusch, K., Möbius, W., Goetze, B., Jahn, H. M., Huang, W., Steffens, H., Schomburg, E. D., Pérez-Samartín, A., Pérez-Cerdá, F., Bakhtiari, D., Matute, C., Löwel, S., Griesinger, C., Hirrlinger, J., Kirchhoff, F., & Nave, K.-A.
- Affiliations
- University of Zurich (CH)
- Max Planck Institute of Experimental Medicine (DE)
- Cleveland Clinic (US)
- Nanoscale Microscopy and Molecular Physiology of the Brain Cluster of Excellence 171 — DFG Research Center 103 (DE)
- University of Göttingen (DE)
- Max Planck Institute for Biophysical Chemistry (DE)
- University of the Basque Country (ES)
- Corresponding author
- Kirchhoff, Frank
- Nave, Klaus-Armin
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2016-07
- Volume
- 91
- Issue
- 1
- Pages
- 119-132
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC9084537
- OpenAlex
- W2419165202
- Semantic Scholar
- 35212334fda129fe29657b347be129741e5f6e4f
- Cited by
- 590
- References
- 60
- Citations by year
- 2026: 48 · 2025: 68 · 2024: 80 · 2023: 61 · 2022: 65 · 2021: 73 · 2020: 58 · 2019: 41 · 2018: 41 · 2017: 45 · 2016: 9
- FWCI
- 25.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- PubMed Central (acceptedVersion)
- GRO (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- National Institute on Aging (R56AG033720, R01AG033720)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- glucose uptake, GLUT1, axonal energy metabolism, myelin, optic nerve, oxygen-glucose deprivation, lactate, glycolysis, glutamate release, myelination
- MeSH terms
- Animals, Axons, Energy Metabolism, Glucose, Mice, Transgenic, Myelin Sheath, Oligodendroglia, Optic Nerve, Oxygen, Receptors, N-Methyl-D-Aspartate, Glucose Transporter Type 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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