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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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“It has been suggested that the changes in ionic homeostasis produced by glutamate uptake might provide the basis for coupling of neuronal activity with metabolism of surrounding astrocytes, which is known as the astrocyte-neuron lactate shuttle hypothesis (Pellerin and Magistretti, 1994).”
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BackgroundPyruvate Protects Neurons against Hydrogen Peroxide-Induced Toxicity
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“Pellerin and Magistretti (1994) have demonstrated that glutamate, which is largely released under ischemia, can stimulate glycolysis in astrocytes and can increase lactate and pyruvate release from these cells.”
BackgroundFueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism
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“201803152 3 For instance, the initial demonstration of feasibility was from separately cultured astrocytes and neurons: glutamate application to cultured astrocytes triggers [3H]-2-deoxyglucose (2-DG; [3H]–2-DG) uptake and lactate release, and neurons are capable of consuming lactate as a fuel (Magistretti et al., 199…”
BackgroundAstrocyte regulation of synaptic behavior
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“Anaerobic glucose metabolism in astrocytes is promoted by the increased synaptic activity in the neuropil to take up excess released glutamate, which is the major transmitter in mammalian CNS (76, 93).”
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“A second possibility is that the transfer of glucose across the blood–brain barrier occurs in the perivascular astrocytic foot processes without the direct transfer of glucose into the extracellular space (Pellerin and Magistretti, 1994), resulting in a net reduction in the extracellular glucose level without a net in…”
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“Long-term memory formation in the hippocampus of these rats was severely impaired upon hippocampal-specific inhibition of either MCT1, MCT2, or MCT4 expression; MCT1 or MCT4 deficiency could be rescued with injection of l-lactate but not equicaloric glucose.”
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“The hypothesis proposed by Pellerin and Magistretti (85) that glutamate recycling in the glutamate-glutamine cycle is tightly coupled to astrocytic glycolysis converting glucose essentially quantitatively to lactate and that this lactate is transferred to neurons for complete oxidation [the astrocyte-neuron-lactate-sh…”
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“Pellerin and Magistretti originally reported that neurons can metabolize lactate originating from astrocytes in vitro (see poster) (Pellerin and Magistretti, 1994).”
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“Studies with primary cultures of astrocytes (Pellerin and Magistretti, 1994; Magistretti et al., 1995) demonstrated the ability of glutamate (Glu) to stimulate glycolysis.”
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“Neuron-Glia metabolic coupling (62–64, 90, 109).”
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“This finding was of interest because the Na,K-ATPase provides the Na gradient for the Na -dependent uptake of GABA, glutamate, and norepinephrine (Inoue and Matsui, 1990; Pellerin and Magistretti, 1994; Masson et al., 1999; Inazu et al., 2003; Munhoz et al., 2005).”
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“In agreement with this, other reports show that astrocytes release pyruvate (Pellerin and Magistretti, 1994) and that neurons can use pyruvate for their function recovery or survival (Selak et al.”
BackgroundResultInfluentialMangia, S., Tkáč, I., Rolf Gruetter, A., de Moortele, P. V., Maraviglia, B., & Uǧurbil, K. (2006) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600401 · Cited by 290
“It is worth noting to remind that our data about Lac cannot either support or disproof the ANLS hypothesis (Pellerin and Magistretti, 1994) because of the inability of in vivo 1 H NMR spectroscopy to differentiate the contributions of the neuronal and astrocytic compartments.”
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Lactate: A Preferred Fuel for Human Brain Metabolism in Vivo
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“Lactate is produced locally within the brain by astrocytes, in an activity-dependent glutamate-mediated manner (Pellerin and Magistretti, 1994).”
BackgroundGlucose, lactate, and shuttling of metabolites in vertebrate retinas
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Lactate as a Metabolite and a Regulator in the Central Nervous System
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“Finally, and most important, since many years ago, the existence of an astrocyte-neuron lactate shuttle (ANLS), which should be particularly active during excitatory neurotransmission, has been suggested [65].”
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Delayed cerebral vasospasm and nitric oxide: review, new hypothesis, and proposed treatment
Pluta, R. M. (2004) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2004.10.002 · Cited by 275
Roles of glutamine in neurotransmission
Albrecht, J., Sidoryk-Węgrzynowicz, M., Zielińska, M., & Aschner, M. (2010) · Neuron Glia Biology · doi:10.1017/s1740925x11000093 · Cited by 273
“Simultaneous measurements from [1-C] glucose into the Glu and Gln pools have demonstrated that the rate of glucose oxidation increases in a 1:1 molar stoichiometric relationship with the Glu/Gln cycle in the rat cerebral cortex, suggesting a common mechanism for these fluxes (Pellerin and Magistretti, 1994; Sibson et…”
Astrocytes in the initiation and progression of epilepsy
Vezzani, A., Ravizza, T., Bedner, P., Aronica, E., Steinhäuser, C., & Boison, D. (2022) · Nature Reviews Neurology · doi:10.1038/s41582-022-00727-5 · Cited by 272
Pellerin, L., Halestrap, A. P., & Pierre, K. (2004) · Journal of Neuroscience Research · doi:10.1002/jnr.20307 · Cited by 269
Self-citationEnergy matters: presynaptic metabolism and the maintenance of synaptic transmission
Li, S., & Sheng, Z. (2021) · Nature reviews. Neuroscience · doi:10.1038/s41583-021-00535-8 · Cited by 285
NAD + as a metabolic link between DNA damage and cell death
Ying, W., Alano, C. C., Garnier, P. E., & Swanson, R. A. (2004) · Journal of Neuroscience Research · doi:10.1002/jnr.20289 · Cited by 269
“Once in brain, glucose may be metabolized directly by neurons and glia or may be metabolized to lactate in glia and the lactate subsequently shuttled to neurons for oxidative metabolism (Dringen et al., 1993; Pellerin and Magistretti, 1994; Wender et al., 2000; Dienel and Cruz, 2004).”
BackgroundMultifunctional role of astrocytes as gatekeepers of neuronal energy supply
Stobart, J. L., & Anderson, C. M. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00038 · Cited by 280
“Astrocytes surveying synaptic activity respond with elevated glucose utilization, glycolysis (Pellerin and Magistretti, 1994; Cholet et al., 2001), and lactate production (Pellerin and Magistretti, 1994; Schurr et al., 1999; Voutsinos-Porche et al., 2003; Caesar et al., 2008).”
BackgroundInfluentialNeuroenergetics: Calling Upon Astrocytes to Satisfy Hungry Neurons
Pellerin, L., & Magistretti, P. J. (2004) · The Neuroscientist · doi:10.1177/1073858403260159 · Cited by 268
Self-citationGLIA-NEURON INTERCOMMUNICATIONS AND SYNAPTIC PLASTICITY
Vernadakis, A. (1996) · Progress in Neurobiology · doi:10.1016/s0301-0082(96)00012-3 · Cited by 270
Xiang, X., Wind, K., Wiedemann, T., Blume, T., Shi, Y., Briel, N., Beyer, L., Biechele, G., Eckenweber, F., Zatcepin, A., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abe5640 · Cited by 268
“It is tempting to speculate that microglia might metabolically support neurons similar to the well-known astrocyte-neuron lactate shuttle (45) and oligodendrocyteneuron lactate shuttle (46, 47).”
BackgroundBouzier‐Sore, A., Voisin, P., Bouchaud, V., Bezancon, E., Franconi, J., & Pellerin, L. (2006) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2006.05056.x · Cited by 265
“Glutamate, via its uptake and the subsequent increase in intracellular Na+ concentration, causes in cultured astrocytes, an enhancement in GLUT1-mediated glucose transport (Loaiza et al., 2003) as well as a stimulation of aerobic glycolysis (Pellerin & Magistretti, 1994).”
BackgroundSelf-citationGoodman, J. C., Valadka, A. B., Gopinath, S. P., Uzura, M., & Robertson, C. S. (1999) · Critical Care Medicine · doi:10.1097/00003246-199909000-00041 · Cited by 266
Riva, C. E., Logean, E., & Falsini, B. (2004) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2004.07.002 · Cited by 265
Oxidative Stress and Beta Amyloid in Alzheimer’s Disease. Which Comes First: The Chicken or the Egg?
Tamagno, E., Guglielmotto, M., Vasciaveo, V., & Tabaton, M. (2021) · Antioxidants · doi:10.3390/antiox10091479 · Cited by 282
“This phenomenon, termed the astrocyte-to-neuron lactate shuttle (ANLS), was first described by Pellerin and Magistretti in the 1990s [155] and is supported by accumulating evidence [156,157].”
BackgroundThe brain as an insulin-sensitive metabolic organ
Milstein, J. L., & Ferris, H. A. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101234 · Cited by 274
“Because astrocytes contribute to neuronal metabolic homeostasis and respond to neuronal firing by releasing lactate [56,105,109], these findings may have implications for astrocyte insulin signaling in maintaining neuronal metabolism and brain metabolic defects observed in insulin-resistant conditions.”
BackgroundBioenergetics and redox adaptations of astrocytes to neuronal activity
Bolaños, J. P. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13486 · Cited by 262
“Therefore, it seems reasonable to move forward and develop therapeutic interventions aimed to interfere with these targets for the treatment of neurological disorders.”
Astrocytes Couple Synaptic Activity to Glucose Utilization in the Brain
Magistretti, P. J., & Pellerin, L. (1999) · Physiology · doi:10.1152/physiologyonline.1999.14.5.177 · Cited by 262
“In 1994, we described (7) a mechanism by which glutamate transport into astrocytes could trigger aerobic glycolysis in these cells, i.”
BackgroundInfluentialSelf-citationEnergy metabolism in ALS: an underappreciated opportunity?
Vandoorne, T., Bock, K. D., & Bosch, L. V. D. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1835-x · Cited by 260
“According to the astrocyte-neuronal lactate shuttle hypothesis, lactate is provided to neurons by astrocytes [147].”
BackgroundSchurr, A., Payne, R. S., Miller, J. J., & Rigor, B. M. (1997) · Brain Research · doi:10.1016/s0006-8993(96)01106-7 · Cited by 262
Pleiotropic Mitochondria: The Influence of Mitochondria on Neuronal Development and Disease
Rangaraju, V., Lewis, T. L., Hirabayashi, Y., Bergami, M., Motori, E., Cartoni, R., Kwon, S., & Courchet, J. (2019) · Journal of Neuroscience · doi:10.1523/jneurosci.1157-19.2019 · Cited by 271
“…restricted to glia, given the central function of these cells in supplying energy metabolites to neurons for fueling synaptic transmission (Pellerin and Magistretti, 1994; Bélanger et al., 2011; Fünfschilling et al., 2012) and their competence in sustaining glycolytic metabolism for…”
BackgroundLoaiza, A., Porras, O. H., & Barros, L. F. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-19-07337.2003 · Cited by 254
“Acute exposure to glutamate causes a twofold increase in hexose utilization by cultured astrocytes, a mechanism that is pivotal in the model of neuron–astrocyte metabolic coupling first advanced by Pellerin and Magistretti (1994).”
InfluentialTolias, C. M., Reinert, M., Seiler, R. W., Gilman, C. B., Scharf, A., & Bullock, M. R. (2004) · Journal of neurosurgery · doi:10.3171/jns.2004.101.3.0435 · Cited by 257
Mitochondrial Transporters as Novel Targets for Intracellular Calcium Signaling
Satrústegui, J., Pardo, B., & del Arco, A. (2007) · Physiological Reviews · doi:10.1152/physrev.00005.2006 · Cited by 261
Do active cerebral neurons really use lactate rather than glucose?
Chih, C.-P., Lipton, P., & Roberts, E. L. (2001) · Trends in Neurosciences · doi:10.1016/s0166-2236(00)01920-2 · Cited by 252
Glial cells in amyotrophic lateral sclerosis
Philips, T., & Rothstein, J. D. (2014) · Experimental Neurology · doi:10.1016/j.expneurol.2014.05.015 · Cited by 266
“Under conditions of increased neuronal activity and metabolic substrate demand, astrocytes increase their glycolytical activity, converting glucose to lactate (Pellerin and Magistretti, 1994).”
BackgroundNeuroimaging in amyotrophic lateral sclerosis: insights into structural and functional changes
Chiò, A., Pagani, M., Agosta, F., Calvo, A., Cistaro, A., & Filippi, M. (2014) · The Lancet Neurology · doi:10.1016/s1474-4422(14)70167-x · Cited by 253
Programming axonal mitochondrial maintenance and bioenergetics in neurodegeneration and regeneration
Cheng, X., Huang, N., & Sheng, Z. (2022) · Neuron · doi:10.1016/j.neuron.2022.03.015 · Cited by 257
Lactylation, a Novel Metabolic Reprogramming Code: Current Status and Prospects
Chen, A.-N., Luo, Y., Yang, Y.-H., Fu, J.-T., Geng, X.-M., Shi, J.-P., & Yang, J. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.688910 · Cited by 324
“As a consequence, glycolysis is in turn stimulated in astrocytes and then lactate moves outward through MCT4 into the extracellular space, driving lactate influx into the surrounding neurons via MCT2 (35).”
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Antioxidant and bioenergetic coupling between neurons and astrocytes
Fernandez-Fernandez, S., Almeida, A., & Bolaños, J. P. (2012) · Biochemical Journal · doi:10.1042/bj20111943 · Cited by 247
Astrocyte dysfunction in Alzheimer disease
Acosta, C., Anderson, H. D., & Anderson, C. M. (2017) · Journal of Neuroscience Research · doi:10.1002/jnr.24075 · Cited by 262
Lactate in contemporary biology: a phoenix risen
Brooks, G. A., Arevalo, J. A., Osmond, A. D., Leija, R. G., Curl, C. C., & Tovar, A. P. (2022) · The Journal of Physiology · doi:10.1113/jp280955 · Cited by 269
Lactate at the crossroads of metabolism, inflammation, and autoimmunity
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“Indeed, muscle-derived lactate is used by hepatocytes to fuel hepatic gluconeogenesis while astrocytes/neurons in the brain utilise lactate for oxidative metabolism (42, 43).”
BackgroundMagistretti, P. J., & Pellerin, L. (1996) · Cerebral Cortex · doi:10.1093/cercor/6.1.50 · Cited by 243
“Indeed, the increase in glucose utilization evoked by glutamate is completely abolished by preincubation of the cultures with the potent glutamate transporter inhibitor DL-&bm>P-hydroxyaspartate (THA; Pellerin and Magistretti, 1994).”
BackgroundInfluentialSelf-citationLactate and BDNF: Key Mediators of Exercise Induced Neuroplasticity?
Müller, P., Duderstadt, Y., Lessmann, V., & Müller, N. G. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9041136 · Cited by 241
“, proposed an astrocyte-neuronal lactate transport during excitatory neurotransmission [132].”
BackgroundChoi, H. B., Gordon, G. R., Zhou, N., Tai, C., Rungta, R. L., Martinez, J., Milner, T. A., Ryu, J. K., McLarnon, J. G., Tresguerres, M., et al. (2012) · Neuron · doi:10.1016/j.neuron.2012.08.032 · Cited by 254
“We found that Neu applying aglycemic solution induced a gradual alkalinization of intracellular pH in astrocytes (Figure S7).”
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“However, overactivation of AMPK by a large dose of metformin may lead to prolonged astrocytic glycolysis, which results in a progressive acidosis and inhibits the ability of neurons to use lactate as an energy source, thus contributing to neuronal death (Pellerin and Magistretti, 1994).”
BackgroundPierre, K., Pellerin, L., Debernardi, R., Riederer, B., & Magistretti, P. J. (2000) · Neuroscience · doi:10.1016/s0306-4522(00)00294-3 · Cited by 238
Self-citation
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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