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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
Experimental — accuracy not yet measuredIn the citing paper
“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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“Particularly, the notion that astrocytic glutamate uptake stimulates lactate production and release, has spiked intensive research into the coupling of excitatory signaling and metabolism (Magistretti & Allaman, 2018; Pellerin & Magistretti, 1994).”
BackgroundAlzheimer’s Disease and Type 2 Diabetes Mellitus: The Use of MCT Oil and a Ketogenic Diet
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“At high activity level, brain energetics follows the original ANLS hypothesis (Pellerin and Magistretti 1994), 1 The online version of this article contains supplemental data.”
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Requardt, R. P., Hirrlinger, P. G., Wilhelm, F., Winkler, U., Besser, S., & Hirrlinger, J. (2012) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2012.07645.x · Cited by 54
Intracellular ascorbic acid inhibits transport of glucose by neurons, but not by astrocytes
Castro, M. A., Pozo, M. A., Cortés‐Campos, C., García, M. D. L. Á., Concha, I. I., & Nualart, F. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04631.x · Cited by 53
Tsacopoulos, M., Poitry‐Yamate, C. L., & Poitry, S. (1997) · Journal of Neuroscience · doi:10.1523/jneurosci.17-07-02383.1997 · Cited by 53
“Growing evidence suggests that astrocytes, by their physiological interactions with neurons, are involved in mammalian brain function and energy metabolism (Pellerin and Magistretti, 1994).”
BackgroundResultInfluentialDienel, G. A., Liu, K., & Cruz, N. F. (2001) · Journal of Neuroscience Research · doi:10.1002/jnr.10063 · Cited by 53
Gegelashvili, M., Rodriguez-Kern, A., SUNG, L., Shimamoto, K., & Gegelashvili, G. (2007) · Neurochemistry International · doi:10.1016/j.neuint.2006.12.015 · Cited by 53
Neuroprotective Effects of Physical Activity via the Adaptation of Astrocytes
Maugeri, G., D’Agata, V., Magrì, B., Roggio, F., Castorina, A., Ravalli, S., Rosa, M. D., & Musumeci, G. (2021) · Cells · doi:10.3390/cells10061542 · Cited by 56
“In fact, glucose is absorbed by astrocytes that are in close contact with capillaries, and part of it is released by astrocytes as lactate into the extracellular space [58,59].”
BackgroundWang, R., He, M., Ou, X., Xie, X., & Kang, Y. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.662385 · Cited by 54
“Initially being put forward in 1994, the astrocyte– neuron lactate shuttle has changed the opinion that lactate is only an useless waste during the anaerobic metabolism process (33).”
BackgroundHammel, G., Zivkovic, S., Ayazi, M., & Ren, Y. (2022) · Cellular Immunology · doi:10.1016/j.cellimm.2022.104591 · Cited by 55
Breast cancer cell-secreted miR-199b-5p hijacks neurometabolic coupling to promote brain metastasis
Ruan, X., Yan, W., Cao, M., Daza, R. A. M., Fong, M., Yang, K., Wu, J., Liu, X., Palomares, M. R., Wu, X., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48740-0 · Cited by 55
“Nevertheless, an analysis using DIANA tools (TarBase V.8) or rnacentral.org did not support this association.”
Early Detection of Alzheimer’s Disease with PET Imaging
Berti, V., Osorio, R. S., Mosconi, L., Li, Y., Santi, S. D., & de Leon, M. J. (2010) · Neurodegenerative Diseases · doi:10.1159/000289222 · Cited by 53
IFN‐γ and IL‐4 differentially shape metabolic responses and neuroprotective phenotype of astrocytes
Garg, S. K., Kipnis, J., & Banerjee, R. V. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.05872.x · Cited by 52
“By supplying neurons with lactate (Pellerin and Magistretti 1994; Bouzier-Sore et al. 2002; Gladden 2004) and cysteine (Dringen 2000), astrocytes contribute to neuronal energy metabolism (Sokoloff et al. 1996) and to antioxidant capacity.”
BackgroundDiffusion of d-glucose measured in the cytosol of a single astrocyte
Kreft, M., Lukšič, M., Zorec, T. M., Prebil, M., & Zorec, R. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-1219-7 · Cited by 52
Amaral, A. I. (2012) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-012-9553-3 · Cited by 52
“…transfer of lactate, which is surrounded by great controversy, evidence exists that it can operate in both directions, through an astrocyte-neuron lactate shuttle (Pellerin and Magistretti 1994; Pellerin et al 1998; Magistretti and Pellerin 1999) or a neuron-astrocyte shuttle (Mangia et al 2009).”
Regulation of cerebral metabolism during cortical spreading depression
Feuerstein, D., Backes, H., Gramer, M., Takagaki, M., Gabel, P., Kumagai, T., & Graf, R. (2015) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x15612779 · Cited by 52
Versatility of microglial bioenergetic machinery under starving conditions
Nagy, Á., Fekete, R., Horváth, G., Koncsos, G., Kriston, C., Sebestyén, A. R., Giricz, Z., Környei, Z., Madarász, E., & Tretter, L. (2017) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2017.12.002 · Cited by 53
“Glycolytic lactate is released from astrocytes and can be taken up by the neurons (Pellerin & Magistretti 1994, Dringen et al. 1993, Schurr et al. 1988).”
BackgroundSynaptic activity‐induced glycolysis facilitates membrane lipid provision and neurite outgrowth
Segarra‐Mondejar, M., Casellas‐Díaz, S., Ramiro‐Pareta, M., Müller‐Sánchez, C., Riera, A. M., Hermelo, I., Reina, M., Aragonés, J., Martínez-Estrada, O. M., & Soriano, F. X. (2018) · The EMBO Journal · doi:10.15252/embj.201797368 · Cited by 64
“The astrocyte-neuron lactate shuttle (ANLS) hypothesis proposes that the lactate produced by astrocytes is released and taken up by neurons to produce energy (Pellerin & Magistretti, 1994).”
Hypoglycemic seizures during transient hypoglycemia exacerbate hippocampal dysfunction
Abdelmalik, P. A., Shannon, P. T., Yiu, A. P., Liang, P., Adamchik, Y., Weisspapir, M., Samoilova, M., Burnham, W. M., & Carlen, P. L. (2007) · Neurobiology of Disease · doi:10.1016/j.nbd.2007.03.002 · Cited by 51
Capillary level imaging of local cerebral blood flow in bicuculline-induced epileptic foci
Hirase, H., Creso, J., & Buzsáki, G. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.07.002 · Cited by 52
Serres, S., Bezançon, E., Franconi, J., & Merle, M. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m409429200 · Cited by 52
Brunet, J. F., Grollimund, L., Chatton, J., Lengacher, S., Magistretti, P. J., Villemure, J., & Pellerin, L. (2003) · Glia · doi:10.1002/glia.10348 · Cited by 52
Self-citationYoo, I. D., Park, M. W., Cha, H. W., Yoon, S., Boonpraman, N., Yi, S. S., & Moon, J.-S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21217862 · Cited by 51
“Astrocytes express the protein of LDHA in the human brain [27,39,41,42].”
BackgroundHalder, S. K., Kant, R., & Milner, R. (2018) · Angiogenesis · doi:10.1007/s10456-017-9593-2 · Cited by 51
“1 3 provide neighboring neurons with the energy substrate lactate, from which neurons then derive ATP [30].”
InfluentialTheriault, J. E., Shaffer, C., Dienel, G. A., Sander, C. Y. M., Hooker, J. M., Dickerson, B. C., Barrett, L. F., & Quigley, K. S. (2023) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2023.105373 · Cited by 60
Effect of fluorocitrate on cerebral oxidation of lactate and glucose in freely moving rats
Zielke, H. R., Zielke, C. L., Baab, P. J., & Tildón, J. T. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04335.x · Cited by 52
“…al. 1983; Roeder et al. 1984), cortical astrocytes (Tildon et al. 1993; Peng et al. 1994; Itoh et al. 2003), primary cultures of cortical neurons (Peng et al. 1994; Bouzier-Sore et al. 2003; Itoh et al. 2003), primary oligodendrocytes (Edmond et al. 1987), isolated synaptosomes (McKenna et al.…”
BackgroundFukushima, M., Lee, S. M., Moro, N., Hovda, D., & Sutton, R. L. (2009) · Journal of Neurotrauma · doi:10.1089/neu.2008.0771 · Cited by 50
“…lactate shuttle (ANLS) will be operative in normal brain tissue to enable uptake and glycolytic processing of glucose by astro-glial cells and the lactate produced can be transferred to neurons to support their metabolic requirements (Pellerin and Magistretti, 1994; Pellerin et al., 2007).”
Agarwal, N., & Renshaw, P. F. (2011) · American Journal of Neuroradiology · doi:10.3174/ajnr.a2587 · Cited by 51
“Second, glutamate uptake triggers glycolysis in astrocytes (aerobic glycolysis) and stimulates synthesis of lactate.(4) The cerebral metabolic rate of glucose oxidation and glutamate neurotransmitter cycling measured by using labeled carbon 13-MRS follows a stoichiometry of 1:1, suggesting a tight relationship between…”
BackgroundMetabolic Crisis in Severely Head-Injured Patients: Is Ischemia Just the Tip of the Iceberg?
Carre, E., Ogier, M., Boret, H., Montcriol, A. A., Bourdon, L., & Risso, J. (2013) · Frontiers in Neurology · doi:10.3389/fneur.2013.00146 · Cited by 51
Brain glucose metabolism: Role of Wnt signaling in the metabolic impairment in Alzheimer’s disease
Cisternas, P., & Inestrosa, N. C. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.06.004 · Cited by 52
“The astrocyte lactate shuttle (ANLS) model has been suggested to explain the compartmentalization of glucose utilization (Pellerin and Magistretti, 1994).”
BackgroundRobinson, M. B., Lee, M. L., & DaSilva, S. (2020) · Neurochemical Research · doi:10.1007/s11064-020-02974-8 · Cited by 52
Wood, J. P. M., Chidlow, G., Graham, M., & Osborne, N. N. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03059.x · Cited by 51
Reduced platelet glutamate uptake in Parkinson's disease
Ferrarese, C., Zoia, C., Pecora, N., Piolti, R., Frigo, M., Bianchi, G., Sala, G., Begni, B., Riva, R., & Frattola, L. (1999) · Journal of Neural Transmission · doi:10.1007/s007020050189 · Cited by 51
“Thus, decreased activity of the Na 1 /K 1 -ATPase, which is necessary for glutamate uptake ( Pellerin and Magistretti, 1994 ), may be responsible for the uptake decrease.”
BackgroundBliss, T. M., & Sapolsky, R. M. (2001) · Brain Research · doi:10.1016/s0006-8993(01)02218-1 · Cited by 52
Chaumeil, M. M., Valette, J., Guillermier, M., Brouillet, E., Boumezbeur, F., Hérard, A., Bloch, G., Hantraye, P., & Lebon, V. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0806516106 · Cited by 51
“Although experimental evidences argue in favor of lactate shuttle having a key role in glutamatergic activation (42, 43), the significance of this shuttle remains controversial (44, 45).”
BackgroundHuman Astrocytes Exhibit Tumor Microenvironment-, Age-, and Sex-Related Transcriptomic Signatures
Krawczyk, M. C., Haney, J. R., Pan, L., Caneda, C., Khankan, R. R., Reyes, S. D., Chang, J. W., Morselli, M., Vinters, H. V., Wang, A., et al. (2022) · Journal of Neuroscience · doi:10.1523/jneurosci.0407-21.2021 · Cited by 51
Metabolism in the progression and metastasis of brain tumors
Tyagi, A., Wu, S.-Y., & Watabe, K. (2022) · Cancer Letters · doi:10.1016/j.canlet.2022.215713 · Cited by 59
“Astrocytes, for example, depend on neuron-derived glutamate to function during metabolic cooperation, whereas neurons, although previously reported to rely on astrocytic lactate, primarily depend on glucose during neuronal stimulation [13,14].”
BackgroundImplications of glial metabolic dysregulation in the pathophysiology of neurodegenerative diseases
Afridi, R., Rahman, M. H., & Suk, K. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105874 · Cited by 53
“coupling between neurons and astrocytes is crucial for brain functioning and is known as the astrocyte–neuron lactate shuttle (Pellerin and Magistretti, 1994).”
BackgroundMethylmalonic acid in aging and disease
Tejero, J. D., Lazure, F., & Gomes, A. P. (2023) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2023.11.001 · Cited by 50
Siegel, C., & McCullough, L. D. (2010) · Acta Physiologica · doi:10.1111/j.1748-1716.2010.02229.x · Cited by 53
Ferrucci, A., Nonnemacher, M. R., & Wigdahl, B. L. (2013) · Journal of NeuroVirology · doi:10.1007/s13365-013-0170-1 · Cited by 50
“By importing extracellular cysteine and glucose, astrocytes synthesize GSH and lactate (respectively) through aerobic glycolysis (Pellerin and Magistretti 1994); they then secrete GSH and lactate, which can be taken up by neurons, thus protecting them from OS.”
BackgroundThe astrocytic contribution to neurovascular coupling – Still more questions than answers?
Kowiański, P., Lietzau, G., Steliga, A., Waśkow, M., & Moryś, J. (2013) · Neuroscience Research · doi:10.1016/j.neures.2013.01.014 · Cited by 60
“The metabolic pathway described above is known as the astrocyte–neuron lactate shuttle hypothesis (Pellerin and Magistretti, 1994; Magistretti et al., 1999).”
BackgroundNormobaric hyperoxia therapy for traumatic brain injury and stroke: a review
Kumaria, A., & Tolias, C. M. (2009) · British Journal of Neurosurgery · doi:10.3109/02688690903050352 · Cited by 52
VanderWall, K. B., Vij, R., Ohlemacher, S. K., Sridhar, A., Fligor, C. M., Feder, E. M., Edler, M. C., Baucum, A. J., Cummins, T. R., & Meyer, J. S. (2019) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.12.010 · Cited by 46
“…with all astrocytes sharing the common function of supporting neurons through the regulation of homeostasis as well as aiding in synaptic formation and maturity (Clarke and Barres, 2013; Eroglu and Barres, 2010; Pellerin and Magistretti, 1994; Pfrieger and Barres, 1997; Ullian et al., 2004).”
BackgroundInfluentialBak, L. K., Obel, L. F., Walls, A. B., Schousboe, A., Faek, S. A. A., Jajo, F. S., & Waagepetersen, H. S. (2012) · ASN NEURO · doi:10.1042/an20120004 · Cited by 45
“tion (Pellerin and Magistretti, 1994; Pellerin et al., 2007).”
Mazuel, L., Blanc, J., Repond, C., Bouchaud, V., Raffard, G., Déglon, N., Bonvento, G., Pellerin, L., & Bouzier-Sore, A.-K. (2017) · PLoS ONE · doi:10.1371/journal.pone.0174990 · Cited by 44
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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