The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index.
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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Citations
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Lamigeon, C., Bellier, J. P., Sacchettoni, S., Rujano, M., & Jacquemont, B. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00278.x · Cited by 41
Glucose and lactate as metabolic constraints on presynaptic transmission at an excitatory synapse
Lucas, S. J., Michel, C. B., Marra, V., Smalley, J. L., Hennig, M. H., Graham, B. P., & Forsythe, I. D. (2018) · The Journal of Physiology · doi:10.1113/jp275107 · Cited by 39
“Another study suggested that the ANLS is required for fully functional 708 synaptic transmission (Nagase et al., 2014), however, 1 mM of the MCT inhibitor 4-709 CIN used in that study would be sufficient to also disrupt mitochondrial pyruvate 710 uptake (McKenna et al., 2001) compromising Krebs cycle ATP production.”
BackgroundInfluentialSpäte, E., Zhou, B., Sun, T., Kusch, K., Asadollahi, E., Siems, S. B., Depp, C., Werner, H. B., Saher, G., Hirrlinger, J., et al. (2024) · Glia · doi:10.1002/glia.24533 · Cited by 40
A role for CO2 and bicarbonate transporters in metabolic exchanges in the brain
Deitmer, J. W. (2002) · Journal of Neurochemistry · doi:10.1046/j.0022-3042.2002.00765.x · Cited by 36
H. Swerdlow, R. (2011) · Current Pharmaceutical Design · doi:10.2174/138161211798072535 · Cited by 35
“There is an emerging realization that neuron and astrocyte energy metabolism are intricately linked [289, 290, 291, 292, 293, 294].”
BackgroundAstrocyte-Neuron Interactions during Learning May Occur by Lactate Signaling Rather than Metabolism
DiNuzzo, M. (2016) · Frontiers in Integrative Neuroscience · doi:10.3389/fnint.2016.00002 · Cited by 31
“In 1994, Pellerin and Magistretti reported that lactate release and concomitant glucose uptake in astrocytic cultures were stimulated by sodium-coupled uptake of glutamate (Pellerin and Magistretti, 1994).”
BackgroundAstrocytic transporters in Alzheimer's disease
Ugbode, C., Hu, Y., Whalley, B., Peers, C., Rattray, M., & Dallas, M. L. (2017) · Biochemical Journal · doi:10.1042/bcj20160505 · Cited by 25
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Wang, N., Zhu, S., Chen, S., Zou, J., Zeng, P., & Tan, S. (2025) · Reviews in the Neurosciences · doi:10.1515/revneuro-2024-0147 · Cited by 12
Farhat, R., Su, G., Sejling, A.-S., Knight, N., Fisher, S. J., & Chan, O. (2019) · Diabetologia · doi:10.1007/s00125-018-4802-0 · Cited by 12
Dynamics of Neuronal and Astrocytic Energy Molecules in Epilepsy
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“Although neurons can also directly take up glucose and neuronal glycolysis has been shown to be the primary source of energy production in neurons in certain situations (Díaz-García et al. 2017; Díaz-García and Yellen 2019), the ANLS likely still plays a role in delivering energy substrates to neurons in other circums…”
Kennedy, L., Morland, C., Narum, M., Bergersen, L. H., & Rinholm, J. E. (2025) · eneuro · doi:10.1523/eneuro.0563-24.2025 · Cited by 8
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Baumart, G. J., Rodrigues, M. S., Sholl, J. N., de Sousa, A. C., Weber, A. F., Costa‐Beber, L. C., Farias, H. R., Costa, M. V., Peres, A. M., de Camargo, P. R., et al. (2026) · Journal of Neurochemistry · doi:10.1111/jnc.70403 · Cited by 2
Energy paradox in REM sleep: balancing supply and consumption in brain metabolism
Takahashi, Y., Ikoma, Y., & Matsui, K. (2026) · Communications Biology · doi:10.1038/s42003-026-10646-6 · Cited by 1
Glucose transporter proteins in brain: Delivery of glucose to neurons and glia
Vannucci, S. J., Maher, F., & Simpson, I. A. (1997) · Glia · doi:10.1002/(sici)1098-1136(199709)21:1
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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