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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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“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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“The first demonstration that glycogen metabolism may involve an astrocyte–neuron interaction was obtained by Magistretti and co-workers, who showed that the release of neurotransmitters from the neuron could induce glycogenolysis in astrocytes [79,80].”
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BackgroundNon-Canonical Control of Neuronal Energy Status by the Na+ Pump
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“The existing view regarding functional hyperemia in the brain is somewhat paradoxical in that it is thought that the delivery of substrate in terms of glucose and oxygen is far in excess of that needed to support neuronal activity (15).”
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“In the brain, this also takes place when oxygen levels are normal, which is referred to as aerobic glycolysis [3].”
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“Glucose is, by far, the major brain energy substrate, and astrocytes participate in matching glucose supply to neuronal energy needs (Pellerin and Magistretti, 1994; Voutsinos-Porche et al., 2003).”
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BackgroundMethodInfluentialInvolvement of Astrocytes in the Formation, Maintenance, and Function of the Blood–Brain Barrier
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“Discussion Effects of MCT inhibition The ANLSH, as described originally (Pellerin and Magistretti, 1994; Magistretti and Pellerin, 1999), has been criticized: glutamate uptake by astrocytes is not coupled uniquely to anaerobic glycolysis, except possibly in cultured cells; it is not clear that there was net flux of la…”
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“…coupling and its underlying physiological and metabolic processes are still incompletely understood; however, their exploration is accelerating (Pellerin and Magistretti, 1994, 2004; Villringer and Dirnagl, 1995; Magistretti and Pellerin, 1999; Magistretti et al., 1999; Obrig et al., 2002;…”
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“glycolysis probably fuels neuron respiration (66).”
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“ronal energy needed for synaptic transmission [72–75].”
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Bauer, D., Jackson, J. G., Genda, E. N., Montoya, M. M., Yudkoff, M., & Robinson, M. B. (2012) · Neurochemistry International · doi:10.1016/j.neuint.2012.01.013 · Cited by 119
“Glutamate uptake into astrocytes may additionally affect metabolism through the stimulation of glycolysis (Bittner et al., 2011; Pellerin and Magistretti, 1994) and glucose transport (Loaiza et al., 2003).”
BackgroundMargineanu, M. B., Mahmood, H., Fiumelli, H., & Magistretti, P. J. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00375 · Cited by 118
Essential Role of Aralar in the Transduction of Small Ca+ Signals to Neuronal Mitochondria
Pardo, B., Contreras, L., Serrano, A., Ramos, M., Kobayashi, K., Iijima, M., Saheki, T., & Satrústegui, J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m507270200 · Cited by 115
Does glutamate image your thoughts?
Bonvento, G., Sibson, N. R., & Pellerin, L. (2002) · Trends in Neurosciences · doi:10.1016/s0166-2236(02)02168-9 · Cited by 116
Self-citationMetabostemness: A New Cancer Hallmark
Menéndez, J. A., & Alarcón, T. (2014) · Frontiers in Oncology · doi:10.3389/fonc.2014.00262 · Cited by 116
The selfish brain: Competition for energy resources
Peters, A. (2010) · American Journal of Human Biology · doi:10.1002/ajhb.21106 · Cited by 121
Takimoto, M., & Hamada, T. (2014) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01288.2013 · Cited by 115
“During brain activation, astrocytic glycolysis accounts for a major portion of the increase in lactate, whereas neurons mostly oxidize the lactate that is released from glial cells (40, 42, 44), suggesting that lactate itself may function as a primary fuel source for neurons.”
BackgroundMicroglial metabolic flexibility: emerging roles for lactate
Monsorno, K., Buckinx, A., & Paolicelli, R. C. (2022) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2021.12.001 · Cited by 115
“One of the best-studied intercellular lactate shuttles refers to the so-called astrocyte–neuron lactate shuttle (ANLS) hypothesis [23,24].”
BackgroundDirect measurement of oxidative metabolism in the living brain by microdialysis: a review
Zielke, H. R., Zielke, C. L., & Baab, P. J. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.05941.x · Cited by 124
Pellerin, L., & Magistretti, P. J. (2004) · Science · doi:10.1126/science.1100428 · Cited by 117
Self-citationJames, J. H., Wagner, K. R., King, J.-K., Leffler, R. E., Upputuri, R. K., Balasubramaniam, A., Friend, L. A., Shelly, D. A., Paul, R. J., & Fischer, J. E. (1999) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1999.277.1.e176 · Cited by 115
“A close relationship between aerobic glycolysis and Na1-K1-ATPase activity has been found in a variety of other cell types, including not only erythrocytes but also Ehrlich ascites tumor cells, neurons, glia, and vascular smooth muscle (16, 26, 33, 34, 36, 39, 46), suggesting that coupling of glycolysis to energy util…”
BackgroundRose, C., & Karus, C. (2013) · Glia · doi:10.1002/glia.22492 · Cited by 112
Allaman, I., & Magistretti, P. J. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-385870-2.00012-3 · Cited by 113
Glucose metabolism and proliferation in glia: role of astrocytic gap junctions
Tabernero, A., Medina, J. M., & Giaume, C. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04088.x · Cited by 114
DOPPENBERG, E. M. R. (1998) · Surgical Neurology · doi:10.1016/s0090-3019(97)00355-8 · Cited by 114
“ter trauma and ischemia [10–14].”
Effects of Subanesthetic Ketamine on Regional Cerebral Glucose Metabolism in Humans
Långsjö, J. W., Salmi, E., Kaisti, K. K., Aalto, S., Hinkka, S., Aantaa, R., Oikonen, V., Viljanen, T., Kurki, T., Silvanto, M., et al. (2004) · Anesthesiology · doi:10.1097/00000542-200405000-00006 · Cited by 123
“The released glutamate must be removed from the synaptic cleft not only to terminate its neurotransmitter effects, but also to prevent extracellular glutamate from reaching excitotoxic concentrations.(34) Astrocytes have been suggested to be primarily responsible for this glucose-consuming uptake of glutamate.”
BackgroundDienel, G. A. (2013) · Neurochemistry International · doi:10.1016/j.neuint.2013.06.015 · Cited by 112
“Astrocyte-to-neuron lactate (ANL) transfer-oxidation model Based on their observation that treatment of cultured astrocytes with glutamate stimulated glycolysis and release of lactate, Pellerin and Magistretti (1994) proposed a model for coupling of glucose utilization with neuronal activity.”
BackgroundMethodNijland, P. G., Michailidou, I., Witte, M. E., Mizee, M. R., van der Pol, S. M. A., Hof, B. V. H., Reijerkerk, A., Pellerin, L., van der Valk, P., de Vries, H. E., et al. (2014) · Glia · doi:10.1002/glia.22667 · Cited by 113
Self-citationCytokine-stimulated astrocytes damage human neurons via a nitric oxide mechanism
Chao, C. C., Hu, S., Sheng, W. S., Bu, D.-F., Bukrinsky, M., & Peterson, P. K. (1996) · Glia · doi:10.1002/(sici)1098-1136(199603)16:3 · Cited by 273
Lactate as a biomarker for sleep
Naylor, E., Aillon, D. V., Barrett, B. S., Wilson, G. S., Johnson, D. A., Johnson, D. A., Harmon, H. P., Gabbert, S., & Petillo, P. A. (2012) · SLEEP · doi:10.5665/sleep.2072 · Cited by 112
Connexin-based intercellular communication and astrocyte heterogeneity
Theis, M., & Giaume, C. (2012) · Brain Research · doi:10.1016/j.brainres.2012.06.045 · Cited by 112
The glial perspective of autism spectrum disorders
Zeidán‐Chuliá, F., Salmina, A. B., Malinovskaya, N. A., Noda, M., Verkhratsky, A., & Moreira, J. C. F. (2013) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2013.11.008 · Cited by 116
“glucose utilization and lactate production) in astrocytes (Pellerin and Magistretti, 1994) and increases activity of glucose transporter-1 (GLUT1) (Loaiza et al.”
GJEDDE, A. H., & Marrett, S. (2001) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-200112000-00002 · Cited by 112
“A recent hypothesis postulates that direct glycolytic generation of ATP in astrocytes is the rule rather than the exception during neuronal excitation (Pellerin and Magistretti, 1994; Magistretti et al., 1999).”
BackgroundGurden, H., Uchida, N., & Mainen, Z. F. (2006) · Neuron · doi:10.1016/j.neuron.2006.07.022 · Cited by 114
Coding and Binding of Color and Form in Visual Cortex
Seymour, K. J., Clifford, C. W. G., Logothetis, N. K., & Bartels, A. (2009) · Cerebral Cortex · doi:10.1093/cercor/bhp265 · Cited by 114
Caruso, G., Caraci, F., & Jolivet, R. B. (2019) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2018.12.004 · Cited by 110
“Likewise, in the brain, a lactate shuttle has been postulated between glial cells and neurons (Pellerin and Magistretti, 1994) and has been the subject of numerous experimental and computational studies, including by some of us (Jolivet et al.”
An integrative dynamic model of brain energy metabolism using in vivo neurochemical measurements
Cloutier, M., Bolger, F. B., Lowry, J. P., & Wellstead, P. E. (2009) · Journal of Computational Neuroscience · doi:10.1007/s10827-009-0152-8 · Cited by 111
“2d: vPFK g); this is coherent with the actual literature on brain metabolism, as glycolysis in astrocytes is activated upon neuronal stimulation (Pellerin and Magistretti 1994; Hyder et al. 2006).”
BackgroundInfluentialCNS Regulation of Glucose Homeostasis
Lam, C., Chari, M., & Lam, T. K. T. (2009) · Physiology · doi:10.1152/physiol.00003.2009 · Cited by 117
“The metabolic fate of brain glucose has been largely clarified by the proposal of the astrocyte-neuron lactate shuttle (96), which is supported by observations that neuronal activity is coupled to glucose utilization (54, 95, 105, 120) and that neurons preferentially utilize glial glucosederived lactate as an oxidativ…”
BackgroundLactate administration reproduces specific brain and liver exercise‐related changes
Lezi, E., Lu, J., Selfridge, J. E., Burns, J. M., & Swerdlow, R. H. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12394 · Cited by 115
Neurons rely on glucose rather than astrocytic lactate during stimulation
Díaz‐García, C. M., & Yellen, G. (2018) · Journal of Neuroscience Research · doi:10.1002/jnr.24374 · Cited by 107
“…alone (Bak et al., 2009), cultured astrocytes can also metabolize glucose and secrete lactate, particularly upon stimulation, and cultured neurons are capable of oxidizing lactate that is supplied to them exogenously (Magistretti, Sorg, Yu, Martin, & Pellerin, 1993; Pellerin & Magistretti, 1994).”
BackgroundNeuroprotective role of lactate in rat neonatal hypoxia-ischemia
Roumes, H., Dumont, U., Sanchez, S., Mazuel, L., Blanc, J., Raffard, G., Chateil, J., Pellerin, L., & Bouzier‐Sore, A. (2020) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x20908355 · Cited by 114
“In this shuttle, glutamate, a neurotransmitter released by neurons during brain activity, is taken up by astrocytes and its entry stimulates the production of glycolytic lactate, which will be transferred to neurons in which it will be used as an energetic substrate.(16,50) While still debated,(20,51) a growing number…”
BackgroundSelf-citationBergersen, L. H. (2004) · Cerebral Cortex · doi:10.1093/cercor/bhh138 · Cited by 111
“…mossy fibre synapses (stratum lucidum and the dentate hilus; for identification criteria of mossy fibre synapses, seeBergersen etal., 2003) aswell as inparallel fibre--Purkinje cell synapses of the cerebellum (for identification criteria of parallel fibre synapses, see Bergersen et al., 2001).”
BackgroundRegulation of glial metabolism studied by 13C‐NMR
Zwingmann, C., & Leibfritz, D. (2003) · NMR in Biomedicine · doi:10.1002/nbm.850 · Cited by 110
Cancer‐like metabolism of the mammalian retina
Ng, S. K., Wood, J. P., Chidlow, G., Han, G., Kittipassorn, T., Peet, D. J., & Casson, R. J. (2014) · Clinical and Experimental Ophthalmology · doi:10.1111/ceo.12462 · Cited by 113
“is calibrated by neuronal activity.(90) There is evidence for and against this hypothesis, and the matter remains highly controversial.”
MethodResultA Systematic Review of Proton Magnetic Resonance Spectroscopy Findings in Sport-Related Concussion
Gardner, A. J., Iverson, G. L., & Stanwell, P. (2013) · Journal of Neurotrauma · doi:10.1089/neu.2013.3079 · Cited by 109
“The in-vivo signal from lactate is observed as a doublet at 1.33ppm. Lac is one marker for energy metabolism, with Lac generated and released by astrocytes thought to serve as an energy substrate for neurons, especially during synaptic activity 34 and during re-oxygenation after stroke.”
Sotero, R. C., & Trujillo‐Barreto, N. J. (2007) · NeuroImage · doi:10.1016/j.neuroimage.2006.10.027 · Cited by 109
“, 1999), combined with studies in isolated astrocytes (Pellerin and Magistretti, 1994) have provided a”
BackgroundMethodXue, X., Liu, B., Hu, J., Bian, X., & Lou, S. (2022) · Nutrition & Metabolism · doi:10.1186/s12986-022-00687-z · Cited by 121
“Based on the findings above, Pellerin and Magistretti proposed the astrocyte-neuron lactate shuttle (ANLS) hypothesis in 1994 [16].”
BackgroundMarcaggi, P., & Coles, J. A. (2001) · Progress in Neurobiology · doi:10.1016/s0301-0082(00)00043-5 · Cited by 112
Brain Anaerobic Lactate Production: A Suicide Note or a Survival Kit?
Schurr, A., & Rigor, B. M. (1998) · Developmental Neuroscience · doi:10.1159/000017330 · Cited by 109
The intent to exercise influences the cerebral O 2 /carbohydrate uptake ratio in humans
Dalsgaard, M. K., Ide, K., Cai, Y., Quistorff, B., & Secher, N. H. (2002) · The Journal of Physiology · doi:10.1113/jphysiol.2001.013062 · Cited by 109
Glia are the main source of lactate utilized by neurons for recovery of function posthypoxia
Schurr, A., Payne, R. S., Miller, J. J., & Rigor, B. M. (1997) · Brain Research · doi:10.1016/s0006-8993(97)81708-8 · Cited by 109
Glutamate Transport Decreases Mitochondrial pH and Modulates Oxidative Metabolism in Astrocytes
Azarias, G., Perreten, H., Lengacher, S., Poburko, D., Demaurex, N., Magistretti, P. J., & Chatton, J.-Y. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.4378-10.2011 · Cited by 107
Mechanisms for the maintenance and regulation of axonal energy supply
Chamberlain, K. A., & Sheng, Z. (2019) · Journal of Neuroscience Research · doi:10.1002/jnr.24411 · Cited by 111
Rose, C. R., & Ransom, B. R. (1996) · Journal of Neuroscience · doi:10.1523/jneurosci.16-17-05393.1996 · Cited by 108
“…include increased Glu metabolism by the ATP-dependent enzyme glutamine synthetase (Sonnewald et al., 1993) or Na1,K1-ATPase activation (Thompson and Prince, 1986; Erecinska, 1989; Pellerin and Magistretti, 1994), because in both cases H1 is released with ATP breakdown (Hochachka and Mommsen, 1983).”
Background13C NMR of Intermediary Metabolism: Implications for Systemic Physiology
Shulman, R. G., & Rothman, D. L. (2001) · Annual Review of Physiology · doi:10.1146/annurev.physiol.63.1.15 · Cited by 110
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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