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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
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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“Modified from Hertz and Rothman (2016) with permission. based on tissue culture experiments by Pellerin and Magistretti (1994) and Pellerin et al. (1998).”
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Sugiura, Y., Honda, K., Kajimura, M., & Suematsu, M. (2013) · PROTEOMICS · doi:10.1002/pmic.201300047 · Cited by 70
The Selfish Brain: Stress and Eating Behavior
Peters, A., Kubera, B., Hubold, C., & Langemann, D. (2011) · Frontiers in Neuroscience · doi:10.3389/fnins.2011.00074 · Cited by 70
“Pellerin and Magistretti (1994) discovered that astrocytes particularly respond to activity of their neighboring neurons.”
Neurometabolic coupling between neural activity, glucose, and lactate in activated visual cortex
Li, B., & Freeman, R. D. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13143 · Cited by 70
Shinohara, M., Petersen, R. C., Dickson, D. W., & Bu, G. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1086-9 · Cited by 56
“Such data may support the notion that regional distribution of lactate is characterized by astrocytes, a main source of lactate [51].”
BackgroundGlucose utilization: still in the synapse
Stoessl, A. J. (2017) · Nature Neuroscience · doi:10.1038/nn.4513 · Cited by 71
Kuter, K. Z., Olech, Ł., & Głowacka, U. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0529-z · Cited by 73
“This is in agreement with the supportive role of astrocytes and metabolic coupling between neurons and astrocytes, proposed previously [28, 69].”
ResultRuminot, I., Schmälzle, J., Leyton, B., Barros, L. F., & Deitmer, J. W. (2017) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x17737012 · Cited by 73
Glycolysis-Derived Compounds From Astrocytes That Modulate Synaptic Communication
Gonçalves, C., Rodrigues, L., Bobermin, L. D., Zanotto, C., Vizuete, A. F. K., Quincozes‐Santos, A., Souza, D. O., & Leite, M. C. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.01035 · Cited by 72
Monitoring of Cerebral Blood Flow and Metabolism in Traumatic Brain Injury
Soustiel, J. F., Glenn, T. C., Shik, V., Boscardin, W. J., Mahamid, E., & Zaaroor, M. (2005) · Journal of Neurotrauma · doi:10.1089/neu.2005.22.955 · Cited by 70
“This concept, however, has been recently challenged by several experimental studies, suggesting the existence of a metabolic coupling between astrocytes and neurons (Pel-lerin, 2003; Pellerin and Magistretti, 1994; Tsacopoulos and Magistretti, 1996).”
Functional Imaging Studies: Linking Mind and Basic Neuroscience
Shulman, R. G. (2001) · American Journal of Psychiatry · doi:10.1176/appi.ajp.158.1.11 · Cited by 70
Estellés, A., Yokoyama, M., Nothias, F., Vincent, J., Glowinski, J., Vernier, P., & Chneiweiss, H. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.25.14800 · Cited by 70
GLP-1 Receptor Agonists in Neurodegeneration: Neurovascular Unit in the Spotlight
Monti, G., Moreira, D. G., Richner, M., Mutsaers, H. A. M., Ferreira, N., & Jan, A. (2022) · Cells · doi:10.3390/cells11132023 · Cited by 72
Cruz, N. F., Ball, K. K., & Dienel, G. A. (2007) · Journal of Neuroscience Research · doi:10.1002/jnr.21193 · Cited by 69
Flavoprotein autofluorescence imaging in the cerebellar cortex in vivo
Reinert, K. C., Gao, W., Chen, G., & Ebner, T. J. (2007) · Journal of Neuroscience Research · doi:10.1002/jnr.21348 · Cited by 71
Why glucose transport in the brain matters for PET
Barros, L. F., Porras, O. H., & Bittner, C. X. (2005) · Trends in Neurosciences · doi:10.1016/j.tins.2005.01.002 · Cited by 72
The role of astrocytes in CNS tumors: pre-clinical models and novel imaging approaches
O’Brien, E. R., Howarth, C., & Sibson, N. R. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00040 · Cited by 71
“Under normal conditions, it has been proposed that the ATP requirements of astrocytes are primarily served by glycolysis (Pellerin and Magistretti, 1994, 1997), with the end-product, lactate, extruded into the extracellular space either for uptake by neurons (Aubert et al., 2005) or clearance from…”
BackgroundConnexin-based channels contribute to metabolic pathways in the oligodendroglial lineage
Niu, J., Li, T., Yi, C., Huang, N., Koulakoff, A., Weng, C., Li, C., Zhao, C., Giaume, C., & Xiao, L. (2016) · Journal of Cell Science · doi:10.1242/jcs.178731 · Cited by 70
“It is well known that astrocytes are the major energy source for neurons because they take up glucose through Gluts and provide the metabolite lactate for neurons through the ‘MCT-mediated astrocyte neuron lactate shuttle’ (Pellerin and Magistretti, 1994, 2012).”
BackgroundFunctional magnetic resonance imaging
Buchbinder, B. R. (2016) · Handbook of clinical neurology · doi:10.1016/b978-0-444-53485-9.00004-0 · Cited by 75
Mitochondrial function in Müller cells - Does it matter?
Toft‐Kehler, A. K., Skytt, D. M., Svare, A., Lefevere, E., Hove, I. V., Moons, L., Waagepetersen, H. S., & Kolko, M. (2017) · Mitochondrion · doi:10.1016/j.mito.2017.02.002 · Cited by 69
Tsai, S., Ku, N., Wang, T.-F., Yang, Y.-H., Shih, Y., Wu, S.-Y., Lee, C.-W., Yu, M., Yang, T.-T., & Kuo, Y. (2018) · Gerontology · doi:10.1159/000488589 · Cited by 69
Measurement of lactate levels in postmortem brain, iPSCs, and animal models of schizophrenia
Sullivan, C. R., Mielnik, C. A., Funk, A., O'Donovan, S. M., Bentea, E., Pletnikov, M. V., Ramsey, A. J., Wen, Z., Rowland, L. M., & McCullumsmith, R. E. (2019) · Scientific Reports · doi:10.1038/s41598-019-41572-9 · Cited by 69
The mechanisms that underlie glucose sensing during hypoglycaemia in diabetes
McCrimmon, R. J. (2008) · Diabetic Medicine · doi:10.1111/j.1464-5491.2008.02376.x · Cited by 72
Exciting Complexity: The Role of Motor Circuit Elements in ALS Pathophysiology
Gunes, Z. I., Kan, V. W. Y., Ye, X., & Liebscher, S. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00573 · Cited by 74
Lactate Supply Overtakes Glucose When Neural Computational and Cognitive Loads Scale Up
Dembitskaya, Y., Piette, C., Siaume‐Perez, S., Berry, H., Magistretti, P. J., & Venance, L. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2212004119 · Cited by 70
Wagner, G., Herbsleb, M., de la Cruz, F., Schumann, A., Brünner, F., Schachtzabel, C., Gussew, A., Puta, C., Smesny, S., Gabriel, H. W., et al. (2015) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2015.125 · Cited by 69
Larsen, T. S., Rasmussen, P. V., Overgaard, M., Secher, N. H., & Nielsen, H. B. (2008) · The Journal of Physiology · doi:10.1113/jphysiol.2008.151449 · Cited by 68
“…concentration (Ide et al. 1999) and it appears to be the cerebral uptake of lactate that determines the reduction in CMR as lactate is transported over the blood–brain barrier by the monocarboxylate transporter (MCT) and shuttled to neurons for aerobic oxidation (Pellerin & Magistretti, 1994).”
BackgroundCerebrospinal Fluid in Long-Lasting Delirium Compared With Alzheimer's Dementia
Caplan, G. A., Kvelde, T., Lai, C., Yap, S. L., Lin, C. S.-Y., & Hill, M. A. (2010) · The Journals of Gerontology Series A · doi:10.1093/gerona/glq090 · Cited by 68
Wang, J., Tu, J., Cao, B., Mu, L., Yang, X., Cong, M., Ramkrishnan, A. S., Chan, R. H. M., Wang, L., & Li, Y. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.11.012 · Cited by 69
Schiera, G., Liegro, C. M. D., & Liegro, I. D. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms21010266 · Cited by 69
“The observation that glutamate released from glutamatergic axons is taken up also by the astrocytes which surround the synapses suggested the existence of an astrocyte–neuron lactate shuttle (ANLS), which should be particularly active during the excitatory neurotransmission [61].”
BackgroundGarcia-Espinosa, M. A., Rodrigues, T. B., Sierra, A., Benito, M., Fonseca, C. P., Gray, H. L., Bartnik‐Olson, B., García‐Martín, M. L., Ballesteros, P., & Cerdán, S. (2004) · Neurochemistry International · doi:10.1016/j.neuint.2003.08.014 · Cited by 68
“An important aspect of the metabolic coupling hypothesis suggested that, lactate produced in the astrocytes by the stim- ulated glycolysis is the main substrate for neuronal oxidative metabolism (Magistretti and Pellerin, 1999a,b; Magistretti et al., 1999; Pellerin et al., 1998).”
ResultStrategies for metabolic exchange between glial cells and neurons
Deitmer, J. W. (2001) · Respiration Physiology · doi:10.1016/s0034-5687(01)00283-3 · Cited by 68
Reactive Astrocytes: Critical Players in the Development of Chronic Pain
Tang, J. D., Bair, M., & Descalzi, G. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.682056 · Cited by 68
Tufm lactylation regulates neuronal apoptosis by modulating mitophagy in traumatic brain injury
Weng, W., He, Z., Ma, Z., Huang, J., Han, Y., Feng, Q., Qi, W., Peng, Y., Wang, J., Gu, J., et al. (2024) · Cell Death and Differentiation · doi:10.1038/s41418-024-01408-0 · Cited by 67
Bélanger, M., Allaman, I., & Magistretti, P. J. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.07135.x · Cited by 71
Astrocyte sodium signaling and neuro-metabolic coupling in the brain
Rose, C. R., & Chatton, J. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.03.002 · Cited by 68
Badaut, J., Ajao, D. O., Sorensen, D. W., Fukuda, A. M., & Pellerin, L. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.10.035 · Cited by 67
“Primary cortical astrocyte-enriched cultures were prepared from mice at postnatal day 1 as previously described (Pellerin and Magistretti, 1994).”
MethodSelf-citationGilsenan, M. B., de Bruin, E. A., & Dye, L. (2009) · British Journal Of Nutrition · doi:10.1017/s0007114508199019 · Cited by 67
“These star-shaped glial cells, which surround neurons and lie in close proximity to the cerebral vasculature, are believed to constitute a likely site of glucose uptake as it crosses the blood–brain barrier (35) .”
BackgroundJha, M. K., Jeon, S., & Suk, K. (2012) · Current Neuropharmacology · doi:10.2174/157015912804143586 · Cited by 71
Jalloh, I., Helmy, A. E., Shannon, R. J., Gallagher, C., Menon, D. K., Carpenter, K. L. H., & Hutchinson, P. J. (2013) · Journal of Neurotrauma · doi:10.1089/neu.2013.2947 · Cited by 67
“13 The concept of lactate functioning as a cerebral energy source has been suggested by Pellerin and Magistretti, 14,15 who in 1994 introduced the principles of a mechanism that later became known as the astrocyte-neuron lactate shuttle (ANLS) hypothesis.”
Brain extracellular glucose assessed by voltammetry throughout the rat sleep–wake cycle
Netchiporouk, L. I., Shram, N. F., Salvert, D., & Cespuglio, R. (2001) · European Journal of Neuroscience · doi:10.1046/j.0953-816x.2001.01503.x · Cited by 67
“A growing body of evidence also points out, nevertheless, that the brain may oxidatively metabolize the lactate produced by glycolysis (Reich et al., 1972; Pellerin & Magistretti, 1994; Hu & Wilson, 1997a; Schurr et al., 1999).”
BackgroundMcKenna, M. C., Tildón, J. T., Stevenson, J., Hopkins, I. B., Huang, X., & Couto, R. (1998) · Developmental Neuroscience · doi:10.1159/000017325 · Cited by 67
In vivo neurochemical monitoring and the study of behaviour
Fillenz, M. (2005) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2005.02.003 · Cited by 67
Lactate/Glucose Dynamics After Rat Fluid Percussion Brain Injury
Chen, T., Qian, Y., Di, X., Rice, A. C., ZHU, J.-P., & Bullock, R. M. (2000) · Journal of Neurotrauma · doi:10.1089/neu.2000.17.135 · Cited by 67
“More recently, Pellerin and Magistretti (1994) showed, in a tissue culture model, that increased ECF glutamate caused lactate production into the ECF space, by astrocytes.”
Influential
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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