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Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization.
Open accessAbstract
Glutamate, released at a majority of excitatory synapses in the central nervous system, depolarizes neurons by acting at specific receptors. Its action is terminated by removal from the synaptic cleft mostly via Na(+)-dependent uptake systems located on both neurons and astrocytes. Here we report that glutamate, in addition to its receptor-mediated actions on neuronal excitability, stimulates glycolysis--i.e., glucose utilization and lactate production--in astrocytes. This metabolic action is mediated by activation of a Na(+)-dependent uptake system and not by interaction with receptors. The mechanism involves the Na+/K(+)-ATPase, which is activated by an increase in the intracellular concentration of Na+ cotransported with glutamate by the electrogenic uptake system. Thus, when glutamate is released from active synapses and taken up by astrocytes, the newly identified signaling pathway described here would provide a simple and direct mechanism to tightly couple neuronal activity to glucose utilization. In addition, glutamate-stimulated glycolysis is consistent with data obtained from functional brain imaging studies indicating local nonoxidative glucose utilization during physiological activation.
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In the citing paper
“Astrocytes are essential CNS cells for glucose uptake (Pellerin and Magistretti 1994; Pellerin 2018).”
From LDL Cholesterol Modulates Astrocyte Metabolism, Lipid Handling, and Morphology: Evidence From In Vitro and In Vivo Models (2026) · cites this paper as Pellerin and Magistretti 1994
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“Lactate taken up by neurons is reconverted into pyruvate and ultimately utilized by mitochondria to generate ATP.”
From Energy paradox in REM sleep: balancing supply and consumption in brain metabolism (2026) · cites this paper as [12]
In the citing paper
“Lactate produced in astrocytes can be released into the extracellular space via monocarboxylate transporters (MCTs). This lactate is subsequently taken up by neurons through neuronal MCTs, a process known as the astrocyte–neuron lactate shuttle (ANLS)12,13.”
From Energy paradox in REM sleep: balancing supply and consumption in brain metabolism (2026) · cites this paper as [12]
In the citing paper
“This may distinguish oligodendrocytes from astrocytes that express LDH and reportedly use a”
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 Pellerin & Magistretti, 1994
In the citing paper
“the calculation of the average metabolic cost per neuron defined here as the total metabolic cost of a structure divided by its number of neurons is justified by the finding that neurons and astrocytes are metabolically coupled [30].”
From Scaling of Brain Metabolism with a Fixed Energy Budget per Neuron: Implications for Neuronal Activity, Plasticity and Evolution (2011) · cites this paper as [30]
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Glial cells in (patho)physiology
Parpura, V., Heneka, M. T., Montana, V., Oliet, S. H. R., Schousboe, A., Haydon, P. G., Stout, R. F., Spray, D. C., Reichenbach, A., Pannicke, T., et al. (2012) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2012.07664.x · Cited by 561
The role of mitochondria in amyotrophic lateral sclerosis
Smith, E. F., Shaw, P. J., & Vos, K. J. D. (2017) · Neuroscience Letters · doi:10.1016/j.neulet.2017.06.052 · Cited by 579
Liu, L., MacKenzie, K. R., Putluri, N., Maletić-Savatić, M., & Bellen, H. J. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.08.024 · Cited by 556
“Along these lines, the Astrocyte Neuron Lactate Shuttle (ANLS) Hypothesis (Pellerin and Magistretti, 1994) was shown to play a role of nervous system homeostasis in Drosophila (Volkenhoff et al., 2015) and mice (Funfschilling et al., 2012; Lee et al., 2012; Machler et al., 2016).”
BackgroundMethylglyoxal, the dark side of glycolysis
Allaman, I., Bélanger, M., & Magistretti, P. J. (2015) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00023 · Cited by 565
“REVIEW ARTICLE published: 09 February 2015 doi: 10.3389/fnins.2015.00023 Methylglyoxal, the dark side of glycolysis”
BackgroundMethodInfluentialKraft, A. D., Johnson, D. A., & Johnson, J. A. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.3817-03.2004 · Cited by 547
“In addition, pyruvate can be further metabolized to lactate, the preferred energy substrate for neurons that helps to maintain synaptic transmission (Pellerin and Magistretti, 1994; Pellerin et al., 1998).”
BackgroundInfluentialLactate is an unreliable indicator of tissue hypoxia in injury or sepsis
James, J. H., Luchette, F. A., McCarter, F. D., & Fischer, J. E. (1999) · The Lancet · doi:10.1016/s0140-6736(98)91132-1 · Cited by 537
Pucino, V., Certo, M., Bulusu, V., Cucchi, D., Goldmann, K., Pontarini, E., Haas, R., Smith, J., Headland, S. E., Blighe, K., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.10.004 · Cited by 555
HYPOXIC-ISCHEMIC ENCEPHALOPATHY
Vannucci, R. C. (2000) · American Journal of Perinatology · doi:10.1055/s-2000-9293 · Cited by 525
Blood lactate is an important energy source for the human brain.
van Hall, G., Stømstad, M., Rasmussen, P., Jans, Ø., Zaar, M., Gam, C., Quistorff, B., Secher, N. H., & Nielsen, H. B. (2009) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2009.35 · Cited by 522
“In cell cultures, neurons metabolize lactate that has been suggested to originate from astrocytic glycolysis, i.e., the astrocyte-to-neuron lactate shuttle (Pellerin and Magistretti, 1994).”
BackgroundWang, D. D., & Bordey, A. (2008) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2008.09.015 · Cited by 538
“coupling between neuronal activation and glucose utilization was proposed, a model known as the astrocyte-neuron lactate shuttle hypothesis (ANLSH) (Pellerin and Magistretti, 1994).”
BackgroundMethodInfluentialImaging cytosolic NADH-NAD(+) redox state with a genetically encoded fluorescent biosensor
Hung, Y. P., Albeck, J. G., Tantama, M., & Yellen, G. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.08.012 · Cited by 509
“Primary Cultured Cortical Astrocytes and Neurons Differ in Their Cytosolic NADH-NAD Redox States Glucose metabolism has been proposed to differ in astrocytes and neurons (Pellerin and Magistretti, 1994; Herrero-Mendez et al., 2009).”
Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons
Yang, J., Ruchti, E., Petit, J.-M., Jourdain, P., Grenningloh, G., Allaman, I., & Magistretti, P. J. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1322912111 · Cited by 504
“Control of L-lactate metabolism in astrocytes as operated by both glutamate- and potassium-mediated glycolysis (28, 31) and by monoamine-mediated glycogenolysis (33) is likely to add another level of regulation of NMDA activity in general and NMDARmediated synaptic plasticity processes in particular.”
BackgroundThe Transcriptome and Metabolic Gene Signature of Protoplasmic Astrocytes in the Adult Murine Cortex
Lovatt, D., Sonnewald, U., Waagepetersen, H. S., Schousboe, A., He, W., Lin, J. H.-C., Han, X., Takano, T., Wang, S., Sim, F. J., et al. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.3404-07.2007 · Cited by 505
“This direct observation speaks to a number of inferential reports to the contrary, which have suggested that astrocytic metabolism is either predominantly (Schurr, 2006) or exclusively (Pellerin and Magistretti, 1994; Sibson et al., 1998; Magistretti et al., 1999; Attwell and Laughlin, 2001) glycolytic.”
BackgroundResting state functional connectivity in preclinical Alzheimer’s disease
Sheline, Y. I., & Raichle, M. E. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.11.028 · Cited by 509
“First, it is critical for glutamate removal from the synaptic cleft into astrocytes(83) by providing ATP to Na/K ATPase, and failure to do so can be damaging through excitotoxic effects of excessive glutamate(84).”
BackgroundThe selfish brain: Competition for energy resources
Peters, A., Schweiger, U., Pellerin, L., Hubold, C., Oltmanns, K. M., Conrad, M., Schultes, B., Born, J., & Fehm, H. L. (2004) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2004.03.002 · Cited by 489
Self-citationAerobic glycolysis in the human brain is associated with development and neotenous gene expression
Goyal, M. S., Hawrylycz, M., Miller, J. A., Snyder, A. Z., & Raichle, M. E. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2013.11.020 · Cited by 459
Brain lactate metabolism: the discoveries and the controversies
Dienel, G. A. (2012) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2011.175 · Cited by 479
“…utilizationa Metabolite oxidation (substrate)a Reference Forebrain, cerebral cortical, or striatal astrocytes 10–500 +15 to +180 +40 to +55 Pellerin and Magistretti, 1994; Takahashi et al, 1995; Debernardi et al, 1999; Chatton et al, 2003 10–1,000 +7 to 60 0 to 27 0 to 60 25 to 75…”
BackgroundMitochondrial dysfunction and oxidative stress in Parkinson's disease and monogenic parkinsonism
Hauser, D. N., & Hastings, T. G. (2012) · Neurobiology of Disease · doi:10.1016/j.nbd.2012.10.011 · Cited by 487
“Neurons are thought to rely more on astrocyte derived lactate as substrates for oxidative phosphorylation, but they continue to be dependent on mitochondrial function for survival (Pellerin and Magistretti, 1994; Wyss et al., 2011).”
BackgroundLactate Produced by Glycogenolysis in Astrocytes Regulates Memory Processing
Newman, L. A., Korol, D. L., & Gold, P. E. (2011) · PLoS ONE · doi:10.1371/journal.pone.0028427 · Cited by 492
“Thus, astrocytic storage of glycogen provides a supplemental energy reserve available to neurons when demand is high [28,29,30,31,32].”
BackgroundLópez-Fabuel, I., Douce, J. L., Logan, A., James, A. M., Bonvento, G., Murphy, M. P., Almeida, Á., & Bolaños, J. P. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1613701113 · Cited by 474
Neuronal Stimulation Triggers Neuronal Glycolysis and Not Lactate Uptake
Díaz-García, C. M., Mongeon, R., Lahmann, C., Koveal, D., Zucker, H., & Yellen, G. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.06.021 · Cited by 466
Stress and depression: possible links to neuron death in the hippocampus
Lee, A. L., Ogle, W. O., & Sapolsky, R. M. (2002) · Bipolar Disorders · doi:10.1034/j.1399-5618.2002.01144.x · Cited by 470
Determination of the rate of the glutamate/glutamine cycle in the human brain by in vivo 13 C NMR
Shen, J., Petersen, K. F., Behar, K. L., Brown, P., Nixon, T. W., Mason, G. F., Petroff, O. A. C., Shulman, G. I., Shulman, R. G., & Rothman, D. L. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.14.8235 · Cited by 462
Hall, C. N., Klein-Flugge, M. C., Howarth, C., & Attwell, D. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.0026-12.2012 · Cited by 451
“When active neurons release glutamate it is taken up into astrocytes, which are proposed to use glycolytically derived ATP to power this uptake and the subsequent conversion of glutamate to glutamine, thus producing lactate which is exported to neurons as a substrate for mitochondrial oxidative phosphorylation (Peller…”
BackgroundElusive roles for reactive astrocytes in neurodegenerative diseases
Ben Haim, L., Carrillo-de Sauvage, M.-A., Ceyzériat, K., & Escartin, C. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00278 · Cited by 453
“It also contributes to synapse formation and neuronal activity; therefore, defects in cholesterol homeostasis may have severe consequences on brain function (Pfrieger and Ungerer, 2011).”
BackgroundA neuron–glia signalling network in the active brain
Bezzi, P., & Volterra, A. (2001) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(00)00223-3 · Cited by 446
Lactate metabolism: historical context, prior misinterpretations, and current understanding
Ferguson, B. S., Rogatzki, M. J., Goodwin, M. L., Kane, D. A., Rightmire, Z. B., & Gladden, L. B. (2018) · European Journal of Applied Physiology · doi:10.1007/s00421-017-3795-6 · Cited by 485
“In contrast, the ANLS hypothesis describes a supportive metabolic milieu in which stimulated neurons release glutamate as an excitatory neurotransmitter (Pellerin and Magistretti 1994, 2003; Pellerin 2003; Bélanger et al. 2011).”
BackgroundIn Vivo Evidence for Lactate as a Neuronal Energy Source
Wyss, M. T., Jolivet, R., Buck, A., Magistretti, P. J., & Weber, B. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.0415-11.2011 · Cited by 451
“Furthermore, astrocytic production of lactate, which serves as an energy pool for neurons, was proposed (Pellerin and Magistretti, 1994), but neuronal lactate use has still to be demonstrated in situ.”
BackgroundEnzyme-Based Biosensors for in Vivo Measurements
Wilson, G. S., & Hu, Y. (2000) · Chemical Reviews · doi:10.1021/cr990003y · Cited by 434
The restless brain: How intrinsic activity organizes brain function
Raichle, M. E. (2015) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2014.0172 · Cited by 433
Role of Monocarboxylate Transporters in Drug Delivery to the Brain
Vijay, N., & Morris, M. (2014) · Current Pharmaceutical Design · doi:10.2174/13816128113199990462 · Cited by 408
“Exposure to glutamate has been shown to stimulate glucose utilization and the release of lactate by astrocytes [69].”
BackgroundMartinez-Outschoorn, U. E., Lisanti, M. P., & Sotgia, F. (2014) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2014.01.005 · Cited by 423
Selective distribution of lactate dehydrogenase isoenzymes in neurons and astrocytes of human brain
Bittar, P. G., Charnay, Y., Pellerin, L., Bouras, C., & Magistretti, P. J. (1996) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-199611000-00001 · Cited by 423
Self-citationBrain Energy and Oxygen Metabolism: Emerging Role in Normal Function and Disease
Watts, M. E., Pocock, R., & Claudianos, C. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00216 · Cited by 438
Lactate released by Muller glial cells is metabolized by photoreceptors from mammalian retina
Poitry‐Yamate, C. L., Poitry, S., & Tsacopoulos, M. (1995) · Journal of Neuroscience · doi:10.1523/jneurosci.15-07-05179.1995 · Cited by 410
“Recent evidence additionally points to the possibility of a cellular compartmentation of lactate metabolism and its trafficking from astroglia to neurones (Dringen et al., 1993; McKenna et al., 1993; Wiesinger et al., 1993; Pellerin and Magistretti, 1994).”
BackgroundNeuronal-glial glucose oxidation and glutamatergic-GABAergic function.
Hyder, F., Patel, A. B., Gjedde, A., Rothman, D. L., Behar, K. L., & Shulman, R. G. (2006) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600263 · Cited by 408
“Studies of glial cultures (Pellerin and Magistretti, 1994) showed that glial glutamate uptake (Flott and Seifert, 1991) cotransported with Na + (Kimelberg et al, 1989) stimulated glial glycolysis and lactate production (Ercinska and Silver, 1987).”
BackgroundCaspase‐3 Mediated Neuronal Death After Traumatic Brain Injury in Rats
Clark, R. S. B., Kochanek, P. M., Watkins, S. C., Chen, M., Dixon, C. E., Seidberg, N. A., Melick, J. A., Loeffert, J. E., Nathaniel, P. D., Jin, K. L., et al. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.740740.x · Cited by 406
Monocarboxylate transporters in the brain and in cancer
Pérez‐Escuredo, J., Hée, V. F. V., Sboarina, M., Falces, J., Payen, V. L., Pellerin, L., & Sonveaux, P. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2016.03.013 · Cited by 415
Self-citationMetabolism and the Control of Circadian Rhythms
Rutter, J. P., Reick, M., & McKnight, S. L. (2002) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.71.090501.142857 · Cited by 405
Metadata
- Authors
- Pellerin, L., & Magistretti, P. J.
- Affiliations
- University of Lausanne (CH)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1994-10-25
- Volume
- 91
- Issue
- 22
- Pages
- 10625-10629
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC45074
- OpenAlex
- W2092635505
- Cited by
- 2,927
- References
- 41
- Citations by year
- 2026: 143 · 2025: 146 · 2024: 138 · 2023: 137 · 2022: 147 · 2021: 168 · 2020: 122 · 2019: 133 · 2018: 109 · 2017: 113 · 2016: 107 · 2015: 116 · 2014: 126 · 2013: 91 · 2012: 88
- FWCI
- 10.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- glutamate uptake, astrocytes, aerobic glycolysis, Na+/K+-ATPase, neuronal activity, glucose utilization, lactic acid production, nonoxidative glucose metabolism, astrocyte-neuron interaction
- MeSH terms
- Sodium-Potassium-Exchanging ATPase, Aerobiosis, Animals, Animals, Newborn, Astrocytes, Biological Transport, Brain, Cells, Cultured, Cerebral Cortex, Deoxyglucose, Glycolysis, Lactates, Models, Neurological, Neurons, Radionuclide Imaging, Tritium, Excitatory Amino Acid Antagonists, Glutamic Acid, Mice
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