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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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“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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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 the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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In the paper
“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
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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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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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
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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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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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
Strength:plain· not yet calibratedn = 3Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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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
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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”
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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
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InfluentialPreparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue.
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InfluentialOligodendroglia metabolically support axons and contribute to neurodegeneration
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InfluentialGlycolytic oligodendrocytes maintain myelin and long-term axonal integrity
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InfluentialSelf-citationNeuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain
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MYELINATION IN RAT BRAIN: METHOD OF MYELIN ISOLATION1
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InfluentialCell death and control of cell survival in the oligodendrocyte lineage
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InfluentialDisruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination
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InfluentialSelf-citation
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“During development, OPCs give rise to oligodendrocytes that generate myelin, which ensures fast signal transmission and provides metabolic support to axons (Nave, 2010; Saab et al., 2016).”
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InfluentialPharmacogenetic stimulation of neuronal activity increases myelination in an axon-specific manner
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“…WMI are mainly associated with impaired cognitive functioning later in life are essential for proper brain connectivity, as myelination enables rapid and efficient propagation of action potentials, and provides protection and trophic support to axons (Funfschilling et al., 2012; Saab et al., 2016).”
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“Previously, myelin has been regarded as an inert and purely insulating membrane, but it is now clear that myelin is metabolically active, providing support to the underlying axon (F€unfschilling et al., 2012; Lee et al., 2012; Saab et al., 2016).”
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Drosophila glia: Few cell types and many conserved functions
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“Myelinating oligodendrocytes can alter action potential propagation speed by regulating potassium levels in the periaxonal space (48) and changing the expression and distribution of molecules involved inmetabolic support of the axon, potentially relevant in setting its maximum firing rate (2, 24).”
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“Over the past 20 years, microglia have been shown to have important functions in regulating the health of myelin, the lipid-rich membrane that surrounds neuronal axons that ensures the rapid propagation of electrical impulses and supports axonal metabolic demands 11,12 .”
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“Moreover, PV+ interneurons are highly energy demanding (Kann et al. 2014), for which myelin provides axonal metabolic support (Fünfschilling et al. 2012; Lee et al. 2012b; Saab et al. 2016).”
BackgroundInfluentialSaltatory Conduction along Myelinated Axons Involves a Periaxonal Nanocircuit
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Self-citationAxo-myelinic neurotransmission: a novel mode of cell signalling in the central nervous system
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“Myelinating oligodendrocytes that are existent behind the optic nerve head also provide metabolic support to axons, besides maintaining the axonal integrity (Saab et al., 2016).”
BackgroundA glycolytic shift in Schwann cells supports injured axons
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“Finally, NMDA glutamate receptors localized in the myelin sheath (Micu et al., 2006, 2016; Saab et al., 2016) can enhance myelination in cell culture (Wake et al.”
InfluentialLoss-or gain-of-function mutations in ACOX1 cause axonal loss via different mechanisms
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“Moreover, the ensheathing OLs can transfer energy substrates into axons (Fünfschilling et al., 2012; Lee et al., 2012b; Saab et al., 2016) possibly supporting them during periods of high metabolic demand.”
BackgroundMonitoring ATP dynamics in electrically active white matter tracts
Trevisiol, A., Saab, A. S., Winkler, U., Marx, G., Imamura, H., Möbius, W., Kusch, K., Nave, K.-A., & Hirrlinger, J. (2017) · eLife · doi:10.7554/elife.24241 · Cited by 151
“The CAP area is proportional to the total number of excited axons and represents a convenient and reliable means of monitoring optic nerve axon function (Stys et al., 1991; Saab et al., 2016).”
BackgroundMethodInfluentialSelf-citationOligodendrocytes in the Mouse Corpus Callosum Maintain Axonal Function by Delivery of Glucose
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The Emerging Role of Central and Peripheral Immune Systems in Neurodegenerative Diseases
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“OLs are myelin-forming cells in the CNS and provide metabolic support to neurons by forming myelin sheaths around axons (Saab et al., 2016).”
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“Recent work from Nave and colleagues further suggests that the mechanism by which glycolysis in oligodendrocytes is matched to different axonal energy needs involves the release of glutamate through axonal activity [46].”
A role of oligodendrocytes in information processing
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“Indeed, stimulation of NMDARs, expressed in immature and mature oligodendrocytes, promote the maturation of these cells and myelination around axons [181–183], upregulates their energy metabolism, increases mitochondria motility within myelin sheath, and glycolytic support to the axons [184, 185].”
BackgroundOligodendroglial fatty acid metabolism as a central nervous system energy reserve
Asadollahi, E., Trevisiol, A., Saab, A. S., Looser, Z. J., Dibaj, P., Ebrahimi, R., Kusch, K., Ruhwedel, T., Möbius, W., Jahn, O., et al. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01749-6 · Cited by 130
“Myelinating oligodendrocytes also provide fast spiking axons with lactate or pyruvate 2–4 for the generation of ATP 5 .”
BackgroundMethodSelf-citationOligodendrocytes express synaptic proteins that modulate myelin sheath formation
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“OLs appear to generate lactate and pyruvate in an activity-dependent manner: glutamate release from neurons activates NMDA receptors on OLs, increasing glucose uptake and lactate production through glycolysis (Saab et al., 2016).”
Heterogeneity of Astrocytes in Grey and White Matter
Köhler, S., Winkler, U., & Hirrlinger, J. (2021) · Neurochemical Research · doi:10.1007/s11064-019-02926-x · Cited by 123
Self-citationNeuron-Oligodendrocyte Interactions in the Structure and Integrity of Axons
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“…through oligodendrogenesis and remyelination with the bulk of remyelination occurring within two weeks in focal chemical models of demyelination (Duncan G. J. et al., 2017) and within two months in cuprizone demyelination (Sachs et al., 2014) and oligodendrocyte depletion (Traka et al., 2010).”
BackgroundAlterations of Oligodendrocyte and Myelin Energy Metabolism in Multiple Sclerosis
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“Indeed, disruption of the axon–myelin unit can occur acutely, such as during transient ischaemia, or chronically in MS and other neurodegenerative diseases, and involve myelinic NMDA receptors, a key component regulating the supply of energy substrates between oligodendrocyte/myelin and axons [134].”
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“Glutamate receptor activation may increase OPC energy supply, promoting their survival, proliferation or differentiation [75,76].”
BackgroundThe contribution of glial cells to Huntington's disease pathogenesis
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Myelinated axon physiology and regulation of neural circuit function
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“, 2016), whereby NMDA receptors, known to be localized to the myelinating processes of oligodendrocytes (Káradóttir & Attwell, 2007), can respond to axonal glutamatergic release and trigger the redistribution of glucose transporters within the myelinating cell to regulate the metabolic support pathways mediated by the…”
BackgroundInfluentialLife-long oligodendrocyte development and plasticity
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“…in dendritic or presynaptic compartments of neurons, or in axons, particularly those in white matter that are surrounded by myelin and seem quite likely to rely on surrounding glial cells (oligodendrocytes) for metabolic support (Meyer et al., 2018; Saab et al., 2016; Trevisiol et al., 2017).”
BackgroundMechanisms for the maintenance and regulation of axonal energy supply
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Oligodendrocyte–axon metabolic coupling is mediated by extracellular K+ and maintains axonal health
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“Glutamatergic signaling has been shown to stimulate the surface expression of glucose transporter 1 (GLUT1) in OLs, suggesting that axonal activity might regulate the metabolic support provided by OLs to axons 10 .”
BackgroundInfluentialSelf-citationStructural and Functional Rescue of Chronic Metabolically Stressed Optic Nerves through Respiration
Harun‐Or‐Rashid, M., Pappenhagen, N., Palmer, P. G., Smith, M. A., Gevorgyan, V., Wilson, G. N., Crish, S. D., & Inman, D. M. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.3652-17.2018 · Cited by 104
“Glucose or lactate is provided to axons through astrocytes or oligodendrocytes (Saab et al., 2016) via glucose and monocarboxylate transporters (MCTs), respectively (Pierre et al., 2002; Simpson et al., 2007).”
BackgroundDecoupling astrocytes in adult mice impairs synaptic plasticity and spatial learning
Hösli, L., Binini, N., Ferrari, K. D., Thieren, L., Looser, Z. J., Zuend, M., Zanker, H. S., Berry, S., Holub, M., Möbius, W., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110484 · Cited by 101
“The extent to which intercellular coupling is reduced inwhitematter tractsof cKOanimals remains tobedetermined, and follow-up studies could further resolve whether alterations in panglial coupling impact axonal physiology and energy homeostasis (Looser et al., 2018; Saab et al., 2016).”
BackgroundSelf-citationDiversity in the oligodendrocyte lineage: Plasticity or heterogeneity?
Foerster, S., Hill, M. F. E., & Franklin, R. J. M. (2019) · Glia · doi:10.1002/glia.23607 · Cited by 103
Oligodendrocyte-encoded Kir4.1 function is required for axonal integrity
Schirmer, L., Möbius, W., Zhao, C., Cruz-Herranz, A., Haim, L. B., Cordano, C., Shiow, L. R., Kelley, K. W., Sadowski, B., Timmons, G. M., et al. (2018) · eLife · doi:10.7554/elife.36428 · Cited by 104
Self-citationMyelin insulation as a risk factor for axonal degeneration in autoimmune demyelinating disease
Schäffner, E., Bosch-Queralt, M., Edgar, J. M., Lehning, M., Strauß, J., Fleischer, N., Kungl, T., Wieghofer, P., Berghoff, S. A., Reinert, T., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01366-9 · Cited by 101
“…from defective axon-glia interactions is in agreement with findings in oligodendroglial mutants 10–13 , and transplantation experiments 14,21,24,25 and is consistent with our understanding of oligodendroglial-mediated mechanisms, such as axonal metabolic support 7–9,26,27 and detoxification 28 .”
ResultSelf-citationDong, X., Zhang, H., Duan, P., Liu, K., Yu, Y., Wei, W., Wang, W., Liu, Y., Cheng, Q., Liang, X., et al. (2023) · Science Advances · doi:10.1126/sciadv.adi1078 · Cited by 101
Oligodendrocytes: Myelination, Plasticity, and Axonal SupportPreprint
Simons, M., Gibson, E. M., & Nave, K. (2024) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a041359 · Cited by 110
Self-citationMetabolic Vulnerability in the Neurodegenerative Disease Glaucoma
Inman, D. M., & Harun-Or-Rashid, M. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00146 · Cited by 88
“The crucial role of MCT1, a mover of energy substrate from the oligodendroglial compartment to axons, in axon function and survival spurred investigation into the regulation of energy exchange between oligodendrocyte and neuron (Saab et al., 2016).”
BackgroundInfluentialFocusing on mitochondria in the brain: from biology to therapeutics
Song, N., Mei, S., Wang, X.-X., Hu, G., & Lu, M. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00409-w · Cited by 111
“They use lactate for their own energy needs and also supply neighbouring axons with lactate [42].”
BackgroundAxonal energy metabolism, and the effects in aging and neurodegenerative diseases
Yang, S., Park, J. H., & Lu, H.-C. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00634-3 · Cited by 94
“Then, glucose is transported into neurons through GLUT3 and GLUT4 [11–14], or imported into oligodendrocytes and microglia through GLUT1 [15, 16]”
BackgroundInfluentialHenn, R. E., Noureldein, M. H., Elzinga, S. E., Kim, B., Savelieff, M. G., & Feldman, E. L. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105766 · Cited by 99
Endothelin signalling mediates experience-dependent myelination in the CNS
Swire, M., Kotelevtsev, Y. V., Webb, D. J., Lyons, D. A., & ffrench‐Constant, C. (2019) · eLife · doi:10.7554/elife.49493 · Cited by 88
Ensheathment and Myelination of Axons: Evolution of Glial Functions
Nave, K., & Werner, H. B. (2021) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-100120-122621 · Cited by 89
Self-citationAddressing neurodegeneration in glaucoma: Mechanisms, challenges, and treatments
Ghanem, G. O. B., Wareham, L. K., & Calkins, D. J. (2024) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2024.101261 · Cited by 103
“Notably, RGC axons can also receive energy metabolites, particularly lactate, from neighboring glial cells like astrocytes and oligodendrocytes (Brown et al., 2003; Saab et al., 2016; Wender et al., 2000).”
G lia in brain energy metabolism: A perspective
Barros, L. F., Brown, A. M., & Swanson, R. A. (2018) · Glia · doi:10.1002/glia.23316 · Cited by 94
“…metabolite flux through oligodendrocytes can in turn be regulated by axonal activity: glutamate activation of NMDA receptors on oligodendrocytes increases their uptake of glucose, which may then be metabolized to lactate and released to axons for oxidative ATP production (Saab et al., 2016).”
BackgroundNodes of Ranvier during development and repair in the CNS
Lubetzki, C., Sol‐Foulon, N., & Desmazières, A. (2020) · Nature Reviews Neurology · doi:10.1038/s41582-020-0375-x · Cited by 95
The tripartite glutamatergic synapse
Lalo, U., Koh, W., Lee, C. J., & Pankratov, Y. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108758 · Cited by 87
Glutamate versus GABA in neuron–oligodendroglia communication
Habermacher, C., Angulo, M. C., & Benamer, N. (2019) · Glia · doi:10.1002/glia.23618 · Cited by 93
“transformed into lactate which is further locally released from OLs toward axons through the monocarboxylate transporter MCT1 expressed at the inner tongue of myelin sheaths (Saab et al., 2016).”
BackgroundInfluentialOligodendrocytes in Alzheimer’s disease pathophysiology
Kedia, S., & Simons, M. (2025) · Nature Neuroscience · doi:10.1038/s41593-025-01873-x · Cited by 86
“This metabolic support must be carefully balanced with axonal energy needs to prevent local acidosis and damage 40,41 .”
Muench, N. A., Patel, S., Maes, M. E., Donahue, R., Ikeda, A., & Nickells, R. W. (2021) · Cells · doi:10.3390/cells10071593 · Cited by 93
Expanding the function of oligodendrocytes to brain energy metabolism
Nave, K., Asadollahi, E., & Sasmita, A. O. (2023) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2023.102782 · Cited by 97
“This led to a working model that oligodendroglial glutamate receptor signaling matches -with some temporal delay-the glycolytic flux and pyruvate/lactate export to axonal energy demands [46].”
BackgroundSelf-citationActivity‐dependent central nervous system myelination throughout life
de Faria, O., Gonsalvez, D. G., Nicholson, M., & Xiao, J. (2018) · Journal of Neurochemistry · doi:10.1111/jnc.14592 · Cited by 90
Pepper, R., Pitman, K. A., Cullen, C. L., & Young, K. M. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00399 · Cited by 86
Myelin plasticity in adulthood and aging
Chapman, T. W., & Hill, R. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.134645 · Cited by 101
Pease-Raissi, S. E., & Chan, J. R. (2021) · Neuron · doi:10.1016/j.neuron.2021.02.003 · Cited by 85
“Activation of oligodendrocyte NMDA receptors upregulates oligodendrocyte glucose uptake, which has been proposed to alter their metabolic support of axons (Saab et al., 2016).”
BackgroundInfluentialRecent insights on astrocyte mechanisms in CNS homeostasis, pathology, and repair
Hart, C. G., & Karimi‐Abdolrezaee, S. (2021) · Journal of Neuroscience Research · doi:10.1002/jnr.24922 · Cited by 88
Myelination generates aberrant ultrastructure that is resolved by microglia
Djannatian, M., Radha, S., Weikert, U., Safaiyan, S., Wrede, C., Deichsel, C., Kislinger, G., Rhomberg, A., Ruhwedel, T., Campbell, D. S., et al. (2022) · The Journal of Cell Biology · doi:10.1083/jcb.202204010 · Cited by 102
“Myelin, produced by oligodendrocytes in the CNS, electrically insulates axons to facilitate saltatory conduction (Rushton, 1951; Cohen et al., 2020; Hartline and Colman, 2007) and also provides metabolic support (Fünfschilling et al., 2012; Lee et al., 2012; Saab et al., 2016).”
BackgroundSelf-citationKetogenic diet ameliorates axonal defects and promotes myelination in Pelizaeus–Merzbacher disease
Stumpf, S. K., Berghoff, S. A., Trevisiol, A., Spieth, L., Düking, T., Schneider, L. V., Schlaphoff, L., Dreha‐Kulaczewski, S. F., Bley, A. E., Burfeind, D., et al. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-01985-2 · Cited by 83
“Electrophysiological recordings were done as described [54, 69].”
BackgroundMethodInfluentialSelf-citationBoda, E. (2021) · European Journal of Neuroscience · doi:10.1111/ejn.14621 · Cited by 80
“…(Bankston, Mandler, & Feng, 2013; Dougherty, Dreyfus, & Black, 2000; Jang, Gould, Xu, Kim, & Kim, 2019; Lee at al., 2012; Philips & Rothstein, 2017; Saab et al., 2016; Wilkins, Majed, Layfield, Compston, & Chandran, 2003) and to the regulation of axonal excitability through K+ buffering (Larson…”
Calcium Signaling in the Oligodendrocyte Lineage: Regulators and Consequences
Paez, P. M., & Lyons, D. A. (2020) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-100719-093305 · Cited by 83
“As noted throughout, OPCs have the ability to respond to neuronal activity, but recent studies have suggested that they might in turn also tune neuronal function by releasing secreted factors (Sakry et al. 2014) and neuromodulators to locally regulate the function of neuronal synapses.”
BackgroundFunctional myelin in cognition and neurodevelopmental disorders
Khelfaoui, H., Ibaceta-González, C., & Angulo, M. C. (2024) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-024-05222-2 · Cited by 87
Stedehouder, J., Brizee, D., Slotman, J. A., Pascual-Garcia, M., Leyrer, M. L., Bouwen, B. L. J., Dirven, C. M. F., Gao, Z., Berson, D. M., Houtsmuller, A. B., et al. (2019) · eLife · doi:10.7554/elife.48615 · Cited by 74
“As myelination has been established to function critically in providing axonal metabolic support (Lee et al., 2012b; Fünfschilling et al., 2012; Saab et al., 2016), myelination of PV+ interneurons could function by helping to optimize axonal energy utilization.”
BackgroundRaffaele, S., Boccazzi, M., & Fumagalli, M. (2021) · Cells · doi:10.3390/cells10030565 · Cited by 90
“GLUT1 upregulation occurs within minutes and augments glucose import, stimulating lactate release [66].”
BackgroundLactate Transporters Mediate Glia-Neuron Metabolic Crosstalk in Homeostasis and Disease
Jha, M. K., & Morrison, B. M. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.589582 · Cited by 81
Central Nervous System Remyelination: Roles of Glia and Innate Immune Cells
Baaklini, C. S., Rawji, K. S., Duncan, G. J., Ho, M. F. S., & Plemel, J. R. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00225 · Cited by 88
Axonal Regulation of Central Nervous System Myelination: Structure and Function
Klingseisen, A., & Lyons, D. A. (2017) · The Neuroscientist · doi:10.1177/1073858417703030 · Cited by 82
Oligodendrogenesis and myelination regulate cortical development, plasticity and circuit function
Fletcher, J. L., Makowiecki, K., Cullen, C. L., & Young, K. M. (2021) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2021.03.017 · Cited by 82
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
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