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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Bradford, M. M. (1976) · Analytical Biochemistry · doi:10.1016/0003-2697(76)90527-3 · Cited by 255,302
Sokoloff, L., Reivich, M., Kennedy, C., Rosiers, M. H. D., Patlak, C. S., Pettigrew, K. D., Sakurada, O., & Shinohara, M. (1977) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1977.tb10649.x · Cited by 6,000
Dynamic magnetic resonance imaging of human brain activity during primary sensory stimulation.
Kwong, K. K., Belliveau, J. W., Chesler, D. A., Goldberg, I. E., Weisskoff, R. M., Poncelet, B. P., Kennedy, D. N., Hoppel, B. E., Cohen, M. S., & Turner, R. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.12.5675 · Cited by 4,212
Ogawa, S., Tank, D. W., Menon, R., Ellermann, J. M., Kim, S. G., Merkle, H., & Ugurbil, K. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.13.5951 · Cited by 3,681
Fox, P. T., & Raichle, M. E. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.4.1140 · Cited by 2,056
Nonoxidative Glucose Consumption During Focal Physiologic Neural Activity
Fox, P. T., Raichle, M. E., Mintun, M. A., & Dence, C. (1988) · Science · doi:10.1126/science.3260686 · Cited by 1,796
Mata, M. M., Fink, D. J., Gainer, H., Smith, C. B., Davidsen, L., Savaki, H. E., Schwartz, W. J., & Sokoloff, L. (1980) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1980.tb04643.x · Cited by 616
Lactate rise detected by 1H NMR in human visual cortex during physiologic stimulation.
Prichard, J. W., Rothman, D. L., Novotny, E. J., Petroff, O. A. C., Kuwabara, T., Avison, M. J., Howseman, A., Hanstock, C. C., & Shulman, R. G. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.13.5829 · Cited by 612
Lactate-supported synaptic function in the rat hippocampal slice preparation.
Schurr, A., West, C. A., & Rigor, B. (1988) · Science · doi:10.1126/science.3375817 · Cited by 594
Glycogen in astrocytes: possible function as lactate supply for neighboring cells
Dringen, R., Gebhardt, R., & Hamprecht, B. (1993) · Brain Research · doi:10.1016/0006-8993(93)91429-v · Cited by 536
Research works printed but not linked: 13
- [9]Yu, N., Martin, J.-L., Stella, N. & Magistretti, P. J. (1993) Proc. Natl. Acad. Sci. USA 90, 4042–4046.
- [12]Pearce, B. (1993) in Astrocytes Pharmacology and Function, ed. Murphy, S. (Academic, San Diego), pp. 47–66.
- [16]Kimelberg, H. K., Jalonen, T. & Walz, W. (1993) in Astrocytes Pharmacology and Function, ed. Murphy, S. (Academic, San Diego), pp. 193–228.
- [18]Lipton, P. & Robacker, K. (1983) Fed. Proc. Fed. Am. Soc. Exp. Biol. 42, 2875–2880.
- [25]Peters, A., Palay, S. L. & Webster, H. DEF. (1991) The Fine Structure of the Nervous System (Oxford Univ. Press, New York), pp. 288, 298–299, 346–353.
- [26]Tsacopoulos, M., Evêquoz-Mercier, V., Perrottet, P. & Buchner, E. (1988) Proc. Natl. Acad. Sci. USA 85, 8727–8731.
- [30]Kadekaro, M., Crane, A. M. & Sokoloff, L. (1985) Proc. Natl. Acad. Sci. USA 82, 6010–6013.
- [31]Kennedy, C., Des Rosiers, M. H., Sakurada, O., Shinohara, M., Reivich, M., Jehle, J. W. & Sokoloff, L. (1976) Proc. Natl. Acad. Sci. USA 73, 4230–4234.
- [33]McIlwain, H. & Bachelard, H. S. (1985) Biochemistry and the Central Nervous System (Churchill Livingstone, Edinburgh), pp. 54–83.
- [40]Prichard, J., Rothman, D., Novotny, E., Petroff, O., Kuwabara, T., Avison, M., Howseman, A., Hanstock, C. & Shulman, R. (1991) Proc. Natl. Acad. Sci. USA 88, 5829–5831.
- [44]Fox, P. T. & Raichle, M. E. (1986) Proc. Natl. Acad. Sci. USA 83, 1140-1144.
- [45]Ogawa, S., Tank, D. W., Menon, R., Ellermann, J. M., Kim, S. G., Merkle, H. & Ugurbil, K. (1992) Proc. Natl. Acad. Sci. USA 89, 5951–5955.
- [46]Kwong, K. K., Belliveau, J. W., Chesler, D. A., Goldberg, I. E., Weisskoff, R. M., Poncelet, B. P., Kennedy, D. N., Hoppel, B. E., Cohen, M. S., Turner, R., Cheng, H.-M., Brady, T. J. & Rosen, B. R. (1992) Proc. Natl. Acad. Sci. USA 89, 5675–5679.
Cited by
Sorted by citations
Items 501–600 of 1,020
DiNuzzo, M., Mangia, S., Maraviglia, B., & Giove, F. (2010) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2010.151 · Cited by 106
“…has posed into question the relative amount of neuronal versus astrocytic glucose uptake (Chih et al, 2001), and is at the basis of the astrocyte–neuron lactate shuttle hypothesis, which places astrocytederived lactate as a critical neuronal energy substrate (Pellerin and Magistretti, 1994).”
Jakoby, P., Schmidt, E. M., Ruminot, I., Gutierrez, R., Barros, L. F., & Deitmer, J. W. (2012) · Cerebral Cortex · doi:10.1093/cercor/bhs309 · Cited by 107
“According to the Astrocyte-to-Neuron Lactate Shuttle Hypothesis (ANLSH; Pellerin and Magistretti 1994), glucose, taken up by astrocytes, is funelled into glycolysis ( partly via the glycogen shunt, see Dringen et al. 1993), and the formed lactate would then be transferred to neurons via…”
Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders
Liu, B., Teschemacher, A. G., & Kasparov, S. (2017) · Glia · doi:10.1002/glia.23136 · Cited by 111
Defects in Bioenergetic Coupling in Schizophrenia
Sullivan, C. R., O'Donovan, S. M., McCullumsmith, R. E., & Ramsey, A. J. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.10.014 · Cited by 108
“Conversely, Pellerin and Magistretti proposed that during increased neuronal activation, glycolysis and lactate production, in astrocytes, predominates that of neurons (“astrocyte-neuron lactate shuttle”) [10-12].”
BackgroundInfluentialThe aerobic brain: lactate decrease at the onset of neural activity
Mangia, S., Garreffa, G., Bianciardi, M., Giove, F., Salle, F. D., & Maraviglia, B. (2003) · Neuroscience · doi:10.1016/s0306-4522(02)00792-3 · Cited by 107
Aerobic glycolysis in the primate brain: Reconsidering the implications for growth and maintenance
Bauernfeind, A. L., Barks, S. K., Duka, T., Grossman, L. I., Hof, P. R., & Sherwood, C. C. (2014) · Brain Structure and Function · doi:10.1007/s00429-013-0662-z · Cited by 105
“…fuel synaptic transmission (see Dienel and Hertz 2001; Hall et al. 2012; Harris et al. 2012; Hertz 2004; Magistretti 2009; Magistretti et al. 1999; Pellerin and Magistretti 1994, 2003), it is not our intention to discuss the relative contributions of oxidative phosphorylation and glycolysis to…”
BackgroundAdapting brain metabolism to myelination and long‐range signal transduction
Hirrlinger, J., & Nave, K. (2014) · Glia · doi:10.1002/glia.22737 · Cited by 109
Martin, C., Houitte, D., Guillermier, M., Petit, F., Bonvento, G., & Gurden, H. (2012) · Frontiers in Neural Circuits · doi:10.3389/fncir.2012.00001 · Cited by 106
“The identification of precise astrocytic mechanisms involved in supply of glucose to active neuronal networks has received much attention for the past couple of decades (Pellerin and Magistretti, 1994; Bonvento et al., 2002; Figley and Stroman, 2011).”
BackgroundBrain energy metabolism: A roadmap for future research
Rae, C. D., Baur, J. A., Borges, K., Dienel, G. A., Díaz‐García, C. M., Douglass, S. R., Drew, K. L., Duarte, J. M. N., Durán, J., Kann, O., et al. (2024) · Journal of Neurochemistry · doi:10.1111/jnc.16032 · Cited by 113
Garg, S. K., Banerjee, R. V., & Kipnis, J. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.6.3866 · Cited by 106
“Activation of the Na /K ATPase depletes astrocytic ATP reserves triggering a shift in energy metabolism toward anaerobic glycolysis (39, 40).”
BackgroundTadi, M., Allaman, I., Lengacher, S., Grenningloh, G., & Magistretti, P. J. (2015) · PLoS ONE · doi:10.1371/journal.pone.0141568 · Cited by 109
“These observations support the view that functional imaging experiments based on glucose analogue extraction may predominantly reflect the metabolic activity of the astrocytic network [5,49].”
BackgroundRudge, J., Pasnikowski, E., Holst, P., & Lindsay, R. M. (1995) · Journal of Neuroscience · doi:10.1523/jneurosci.15-10-06856.1995 · Cited by 105
“The radial glial cells can then transform into astrocytes that are capable of providing energy substrates to more mature neurons under stress by controlling glycogenolysis (Sorg and Magistretti, 1991, 1992; Pellerin and Magistretti, 1994).”
BackgroundHyperglycaemia and Diabetes Impair Gap Junctional Communication among Astrocytes
Gandhi, G. K., Ball, K. K., Cruz, N. F., & Dienel, G. A. (2010) · ASN NEURO · doi:10.1042/an20090048 · Cited by 105
Hypoxia and exercise provoke both lactate release and lactate oxidation by the human brain
Overgaard, M., Rasmussen, P. V., Bohm, A. M., Seifert, T., Brassard, P., Zaar, M., Homann, P. H., Evans, K. A., Nielsen, H. B., & Secher, N. H. (2012) · The FASEB Journal · doi:10.1096/fj.11-191999 · Cited by 102
“Cell-cell shuttling has been demonstrated for muscles and has also been proposed within the brain by the astrocyteneuron lactate shuttle (37), or the alternative neuronastrocyte lactate shuttle (38), but here, we did not Figure 6.”
BackgroundGSEA of mouse and human mitochondriomes reveals fatty acid oxidation in astrocytes
Eraso‐Pichot, A., Brasó‐Vives, M., Golbano, A., Menacho, C., Claro, E., Galea, E., & Masgrau, R. (2018) · Glia · doi:10.1002/glia.23330 · Cited by 105
“This entails the release of glutamate that stimulates glucose uptake and glycolysis rate in astrocytes (Pellerin & Magistretti, 1994).”
BackgroundTanycytic networks mediate energy balance by feeding lactate to glucose-insensitive POMC neurons
Lhomme, T., Clasadonte, J., Imbernón, M., Fernandois, D., Sauvé, F., Caron, É., Lima, N. D. S., Heras, V., Martínez‐Corral, I., Müller‐Fielitz, H., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci140521 · Cited by 111
“Mice lacking pro-opiomelanocortin are sensitive to high-fat feeding but respond normally to the acute anorectic effects of peptide-YY(3-36).”
BackgroundMethodTrafficking of molecules and metabolic signals in the retina
Tsacopoulos, M., Poitry‐Yamate, C. L., MacLeish, P. R., & Poitry, S. (1998) · Progress in Retinal and Eye Research · doi:10.1016/s1350-9462(98)00010-x · Cited by 105
Schuhmann, M., Stiller, D., Skardelly, M., Bernarding, J., Klinge, P., Samii, A., Samii, M., & Brinker, T. (2003) · Journal of Neurotrauma · doi:10.1089/089771503767869962 · Cited by 107
“According to the astrocyte-neu-ron lactate shuttle hypothesis lactate is produced by astrocytes in areas of glutamatergic neuronal excitation (Magistretti and Pellerin, 2000; Pellerin and Magistretti, 1994).”
Dienel, G. A. (2015) · Neuroscience Letters · doi:10.1016/j.neulet.2015.02.052 · Cited by 105
Bouzier‐Sore, A., Thiaudière, E., Biran, M., Rouland, R., Canioni, P., & Merle, M. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.0750480.x · Cited by 105
The inhibitory effects of β-amyloid on glutamate and glucose uptakes by cultured astrocytes
Parpura‐Gill, A., Beitz, D. C., & Uemura, E. (1997) · Brain Research · doi:10.1016/s0006-8993(97)00043-7 · Cited by 105
Marina, N., Ang, R., Machhada, A., Kasymov, V., Karagiannis, A., Hosford, P. S., Mosienko, V., Teschemacher, A. G., Pirkko, V., Paton, J. F. R., et al. (2015) · Hypertension · doi:10.1161/hypertensionaha.114.04683 · Cited by 104
Astrocyte adenosine deaminase loss increases motor neuron toxicity in amyotrophic lateral sclerosis
Allen, S. P., Hall, B., Castelli, L. M., Francis, L. I., Woof, R., Siskos, A., Kouloura, E., Gray, E., Thompson, A. G., Talbot, K., et al. (2019) · Brain · doi:10.1093/brain/awy353 · Cited by 102
Crosstalk between Neuron and Glial Cells in Oxidative Injury and Neuroprotection
Lee, K. H., Cha, M., & Lee, B. H. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413315 · Cited by 104
Jolivet, R., Coggan, J. S., Allaman, I., & Magistretti, P. J. (2015) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1004036 · Cited by 110
“While the ANLS hypothesis, since its initial formulation [5], does not preclude the use of glucose by neurons as an energy substrate, it has been challenged by some studies defending the view that glucose, rather than lactate, is the sole energy substrate for oxidative metabolism in neurons [37, 38].”
BackgroundInfluentialBrix, B., Mesters, J. R., Pellerin, L., & Jöhren, O. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.0879-12.2012 · Cited by 103
“A fast lactate release from astrocytes to activated neurons, as was previously demonstrated to be triggered both by glutamate (Pellerin and Magistretti, 1994) and K (Bittner et al.”
BackgroundMethodSelf-citationMR imaging in the non-human primate: studies of function and of dynamic connectivity
Logothetis, N. K. (2003) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2003.09.017 · Cited by 104
“ygen consumption, and ultimately an oversupply of oxygenated blood [ 2 ,3].”
BackgroundMethodInfluentialFatty acid-induced astrocyte ketone production and the control of food intake
Foll, C. L., & Levin, B. E. (2016) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00113.2016 · Cited by 107
The Strategic Location of Glycogen and Lactate: From Body Energy Reserve to Brain Plasticity
Calì, C., Tauffenberger, A., & Magistretti, P. J. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00082 · Cited by 106
Neuron–glia interaction in the Drosophila nervous system
Bittern, J., Pogodalla, N., Ohm, H., Brüser, L., Kottmeier, R., Schirmeier, S., & Klämbt, C. (2020) · Developmental Neurobiology · doi:10.1002/dneu.22737 · Cited by 104
“This resembles the astrocyte neuron lactate shuttle which describes the metabolic coupling of glial cells and neurons in the mammalian brain (Magistretti & Allaman, 2015; Pellerin & Magistretti, 1994; Rittschof & Schirmeier, 2017; Simons & Nave, 2016; Tsacopoulos & Magistretti, 1996).”
BackgroundLactate is an energy substrate for rodent cortical neurons and enhances their firing activity
Karagiannis, A., Gallopin, T., Lacroix, A., Plaisier, F., Piquet, J., Geoffroy, H., Hepp, R., Naudé, J., Gac, B. L., Egger, R., et al. (2021) · eLife · doi:10.7554/elife.71424 · Cited by 108
McNay, E. C., & Gold, P. E. (2002) · Behavioral and Cognitive Neuroscience Reviews · doi:10.1177/1534582302238337 · Cited by 103
Jalloh, I., Carpenter, K. L. H., Helmy, A. E., Carpenter, T. A., Menon, D. K., & Hutchinson, P. J. (2014) · Metabolic Brain Disease · doi:10.1007/s11011-014-9628-y · Cited by 103
“This has become known as the astrocyte-neuron lactate shuttle hypothesis (Pellerin and Magistretti 1994).”
BackgroundNewington, J. T., Harris, R. A., & Cumming, R. C. (2013) · Journal of Neurodegenerative Diseases · doi:10.1155/2013/234572 · Cited by 109
“The first evidence for the existence of an ANLS was demonstrated by Pellerin and Magistretti in 1994, who showed that glutamate uptake in primary mouse cortical astrocytes stimulated aerobic glycolysis (glucose uptake and lactate production) [16].”
BackgroundSympathetic influence on cerebral blood flow and metabolism during exercise in humans
Seifert, T., & Secher, N. H. (2011) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2011.09.008 · Cited by 104
“…demand for ATP activates astrocytic glycolysis leading to lactate formation that is transported to neurons for oxidation, known as the astrocyte-neuron lactate shuttle hypothesis (Pellerin and Magistretti, 1994) and proposes that lactate is used as an oxidative energy substrate equal to glucose.”
BackgroundTumor-stroma metabolic relationship based on lactate shuttle can sustain prostate cancer progression
Sanità, P., Capulli, M., Teti, A. M., Galatioto, G. P., Vicentini, C., Chiarugi, P., Bologna, M., & Angelucci, A. (2014) · BMC Cancer · doi:10.1186/1471-2407-14-154 · Cited by 102
“Similar energetic symbiosis is present in other organs, such as brain and ovary, also in absence of a rapid energetic expenditure, or hypoxic pressure [24,25].”
BackgroundLei, H. C., Uǧurbil, K., & Chen, W. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2332656100 · Cited by 102
Nair, D. G. (2005) · Brain Research Reviews · doi:10.1016/j.brainresrev.2005.07.001 · Cited by 102
The role of tanycytes in hypothalamic glucosensing
Elizondo-Vega, R. J., Cortés‐Campos, C., Barahona, M. J., Oyarce, K., Pardo, C. C., & García, M. D. L. Á. (2015) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.12590 · Cited by 113
Tefera, T. W., & Borges, K. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00611 · Cited by 100
“In addition, according to the astrocyte-neuron lactate shuttle hypothesis, glutamate stimulated metabolism of glucose in astrocytes produces lactate which can be transferred to neurons to be utilized as fuel (Pellerin and Magistretti, 1994).”
BackgroundThe role of astrocytes and noradrenaline in neuronal glucose metabolism
Fillenz, Lowry, Boutelle, & Fray (1999) · Acta Physiologica Scandinavica · doi:10.1046/j.1365-201x.1999.00578.x · Cited by 101
“However, the stimulated release of lactate both in cultured astrocytes (Pellerin & Magistretti 1994) and in vivo (Fray et al. 1996, Demestre et al. 1997) appears to be dependent on glutamate uptake as it is blocked by glutamate uptake blockers.”
BackgroundWagner, K., Unger, L., Salman, M. M., Kitchen, P., Bill, R. M., & Yool, A. J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031388 · Cited by 97
“ANLS Astrocyte-to-neuron lactate shuttle AQP Aquaporin ar/R Aromatic/arginine BBB Blood–brain barrier CaM Calmodulin cAMP Cyclic adenosine monophosphate cGMP Cyclic guanosine monophosphate CHIP28 Channel-forming integral protein 28 CNS Central nervous system COPD Chronic obstructive pulmonary disease CSF Cerebrospinal…”
BackgroundA conceptual framework for astrocyte function
Murphy‐Royal, C., Ching, S., & Papouin, T. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01448-8 · Cited by 112
“…is the heterogeneous and seemingly unreliable range of cues to which astrocytes react (Supplementary Table 1), and traditional perspectives have offered limited insights into how these disparate observations fit together and what they tell us about the conditions that recruit astrocytes 4,6 .”
BackgroundThe role of glial cells in synaptic function
Bacci, A., Verderio, C., Pravettoni, E., & Matteoli, M. (1999) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.1999.0393 · Cited by 101
“B (1999) glutamate-dependent way and therefore by a synaptic activity-operated mechanism (Pellerin & Magistretti 1994).”
BackgroundInsulin Restores Metabolic Function in Cultured Cortical Neurons Subjected to Oxidative Stress
Duarte, A. I., Proença, T., Oliveira, C. R., Santos, M. S., & Rego, A. C. (2006) · Diabetes · doi:10.2337/db06-0030 · Cited by 100
“The brain is one of the most metabolically active tissues, relying on continuous glucose supply for synaptic transmission and dendritic and axonal trafficking, thus helping to maintain brain cognitive function (6,7).”
BackgroundMethodMolecular and cellular physiology of sodium-dependent glutamate transporters
Rose, C. R., Ziemens, D., Untiet, V., & Fahlke, C. M. (2016) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2016.12.013 · Cited by 100
“Consumption of ATP in response to sodium increases indeed has been shown to enhance glucose uptake and aerobic glycolysis as well as glycogenolysis in cultured astrocytes (Pellerin and Magistretti, 1994; Bernardinelli et al., 2004; Magistretti and Chatton, 2005).”
Hydraulic resistance of periarterial spaces in the brain
Tithof, J., Kelley, D. H., Mestre, H., Nedergaard, M., & Thomas, J. H. (2019) · Fluids and Barriers of the CNS · doi:10.1186/s12987-019-0140-y · Cited by 101
Afridi, R., Kim, J., Rahman, M. H., & Suk, K. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00020 · Cited by 102
Cerebral Lactate Metabolism After Traumatic Brain Injury
Patet, C., Suys, T., Carteron, L., & Oddo, M. (2016) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-016-0638-5 · Cited by 101
Aubert, A., Pellerin, L., Magistretti, P. J., & Costalat, R. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0605864104 · Cited by 98
Self-citationMIRNAS in Astrocyte-Derived Exosomes as Possible Mediators of Neuronal Plasticity
Lafourcade, C., Ramírez, J. P., Luarte, A., Fernández, A., & Wyneken, Ú. (2016) · Journal of Experimental Neuroscience · doi:10.4137/jen.s39916 · Cited by 105
Focusing on mitochondria in the brain: from biology to therapeutics
Song, N., Mei, S., Wang, X.-X., Hu, G., & Lu, M. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00409-w · Cited by 111
“This process largely supports the neuronal energetic needs by supplying metabolic substrates [40, 41].”
BackgroundCalcium Signaling in Brain Mitochondria
Contreras, L., & Satrústegui, J. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m808066200 · Cited by 99
An In Vivo Proton Magnetic Resonance Spectroscopy Study of Schizophrenia Patients
Stanley, J. A., Williamson, P., Drost, D. J., Rylett, R. J., Carr, T. J., MALLA, A. K., & Thompson, R. T. (1996) · Schizophrenia Bulletin · doi:10.1093/schbul/22.4.597 · Cited by 98
Astrocytes in the regulation of cerebrovascular functions
Cohen‐Salmon, M., Slaoui, L., Mazaré, N., Gilbert, A., Oudart, M., Alvear‐Perez, R., Elorza‐Vidal, X., Chever, O., & Boulay, A. (2021) · Glia · doi:10.1002/glia.23924 · Cited by 93
“Glucose (shuttled from the blood to the astrocytes by the transporter GLUT1, where it is converted into lactate) is probably the main energy metabolite for neurons (Pellerin & Magistretti, 1994).”
BackgroundLourenço, C. F., Ledo, A., Barbosa, R. M., & Laranjinha, J. A. N. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.04.026 · Cited by 102
“In particular, glutamate uptake at the astrocytes appears to produce a sodium-dependent signal that couples glutamatergic transmission to increased glucose utilization by astrocytes [90].”
BackgroundOzawa, S., Ueda, S., Imamura, H., Mori, K., Asanuma, K., Yanagita, M., & Nakagawa, T. (2015) · Scientific Reports · doi:10.1038/srep18575 · Cited by 96
Structure and Function of the Blood–Brain Barrier (BBB)
Benz, F., & Liebner, S. (2020) · Handbook of experimental pharmacology · doi:10.1007/164_2020_404 · Cited by 103
Glial Cells as Therapeutic Approaches in Brain Ischemia-Reperfusion Injury
Hernández, I. H., Villa-González, M., Martín-López, G., Soto, M. S., & Pérez-Álvarez, M. J. (2021) · Cells · doi:10.3390/cells10071639 · Cited by 98
“Astrocytes provide neurons with lactate as a precursor for the tricarboxylic acid (TCA) cycle, in a proposed mechanism known as “astrocyte-neuron lactate shuttle hypothesis” [88], which remains controversial [89].”
BackgroundRegenold, W. T., Pratt, M., Nekkalapu, S., Shapiro, P. S., Kristián, T., & Fiskum, G. M. (2011) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2011.09.018 · Cited by 96
Ion changes and signalling in perisynaptic glia
Deitmer, J. W., & Rose, C. R. (2009) · Brain Research Reviews · doi:10.1016/j.brainresrev.2009.10.006 · Cited by 98
“…signals are present in astrocytes following neuronal release of glutamate supports the proposed tight link between excitatory neuronal activity, glutamate transport, sodium homeostasis, pH and glucose utilization by astrocytes (Pellerin and Magistretti, 1994; Tsacopoulos and Magistretti, 1996).”
BackgroundIL-6-type cytokines enhance epidermal growth factor-stimulated astrocyte proliferation
Levison, S. W., Jiang, F., Stoltzfus, O. K., & Ducceschi, M. H. (2000) · Glia · doi:10.1002/1098-1136(200012)32:3 · Cited by 72
Brain aerobic glycolysis functions and Alzheimer’s disease
Vlassenko, A. G., & Raichle, M. E. (2014) · Clinical and Translational Imaging · doi:10.1007/s40336-014-0094-7 · Cited by 96
“It is well established that physiological neural activity stimulates AG in human brain and that the concentration of ISF lactate, a marker of AG, is increased during glutamatergic transmission [48, 86].”
BackgroundEmerging roles of brain metabolism in cognitive impairment and neuropsychiatric disorders
Morella, I., Brambilla, R., & Morè, L. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104892 · Cited by 96
“Based on early evidence, glycolysis was thought to occur in astrocytes to produce lactate, subsequently shuttled to neurons and converted into pyruvate to generate ATP in neuronal mitochondria (Pellerin and Magistretti, 1994).”
Escartin, C., Brouillet, E., Gubellini, P., Trioulier, Y., Jacquard, C., Smadja, C., Knott, G. W., Goff, L. K., Déglon, N., Hantraye, P., et al. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.0302-06.2006 · Cited by 95
“mechanism involving glutamate uptake by glial transporters (Pellerin and Magistretti, 1994).”
InfluentialSun, Y., Wang, Y., Chen, S., Chen, Y., Shen, J., Yao, W., Gao, X., & Chen, S. (2020) · Theranostics · doi:10.7150/thno.44370 · Cited by 95
“In particular, there are many studies supporting the astrocyte-neuron lactate shuttle hypothesis [45-48].”
ResultAxonal energy metabolism, and the effects in aging and neurodegenerative diseases
Yang, S., Park, J. H., & Lu, H.-C. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00634-3 · Cited by 94
“Because LDH-B favors the conversion in reverse direction to LDH-A, that is it consumes NAD+ and produces NADH and pyruvate [291, 292], LDH-B’s activity may counteract LDH-A, thus reducing NAD redox potential and restraining glycolysis.”
BackgroundBehavioral and neurochemical effects of proline
Wyse, Â. T. D. S., & Netto, C. A. (2011) · Metabolic Brain Disease · doi:10.1007/s11011-011-9246-x · Cited by 93
“Such sodium elevations stimulate Na,K-ATPase and cause increased ATP consumption and glucose uptake by astrocytes (Chatton et al. 2000; Loaiza et al. 2003; Pellerin and Magistretti 1994; Porras et al. 2008).”
BackgroundDiNuzzo, M., Mangia, S., Maraviglia, B., & Giove, F. (2009) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2009.232 · Cited by 93
“The critical observation that glutamate can induce glucose uptake and lactate release in cultured astrocytes (Pellerin and Magistretti, 1994), although not observed in many astrocyte preparations (Dienel and Cruz, 2004), provided adequate ground for the astrocyte-neuron lactate shuttle (ANLS)…”
BackgroundCurrent Challenges for the Early Detection of Alzheimer's Disease: Brain Imaging and CSF Studies
Mistur, R. L., Mosconi, L., Santi, S. D., Guzman, M., Li, Y., Tsui, W., & de Leon, M. J. (2009) · Journal of Clinical Neurology · doi:10.3988/jcn.2009.5.4.153 · Cited by 101
“that coupling between energy metabolism and neuronal activity may also be achieved through astrocytic uptake of glucose and lactate shuttling to neurons.(33)”
BackgroundReinert, M., Khaldi, A., Zauner, A., DOPPENBERG, E. M. R., Choi, S. C., & Bullock, R. M. (2000) · Journal of neurosurgery · doi:10.3171/jns.2000.93.5.0800 · Cited by 94
Hemichannel-mediated release of lactate
Karagiannis, A., Sylantyev, S., Hadjihambi, A., Hosford, P. S., Kasparov, S., & Gourine, A. V. (2015) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x15611912 · Cited by 98
“The so-called ‘astrocyte-to-neuron lactate shuttle’ hypothesis suggests that neuronal activity is fuelled by lactate provided by neighbouring astrocytes.(1,2) Although there is evidence which argues against the importance (and existence) of astrocyte-to-neuron lactate shuttle (for a comprehensive review see Dienel(3))…”
Circadian blueprint of metabolic pathways in the brain
Greco, C. M., & Sassone‐Corsi, P. (2018) · Nature reviews. Neuroscience · doi:10.1038/s41583-018-0096-y · Cited by 94
Gollihue, J. L., & Norris, C. M. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101039 · Cited by 93
“Despite their heavy reliance on glycolysis for energy production (Hamberger and Hyden, 1963; Pellerin and Magistretti, 1994; Zhang et al., 2014), astrocytes are responsible for 20% of the brain’s total oxygen consumption (Bluml et al.”
BackgroundHenn, R. E., Noureldein, M. H., Elzinga, S. E., Kim, B., Savelieff, M. G., & Feldman, E. L. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105766 · Cited by 99
“Metabolic interaction partially explains this discrepancy; astrocytes sense glutamate, a surrogate of neuronal activity, which enhances their glucose consumption and subsequent lactate release to neurons through the astrocyte-neuron lactate shuttle (Pellerin and Magistretti 1994).”
BackgroundAstroglial Pentose Phosphate Pathway Rates in Response to High-Glucose Environments
Takahashi, S., Izawa, Y., & Suzuki, N. (2012) · ASN NEURO · doi:10.1042/an20120002 · Cited by 93
“Moreover, a long-lasting debate exists regarding the ANLSH (astrocyteneuron lactate shuttle hypothesis) (Pellerin and Magistretti, 1994; Magistretti et al., 1999; Chih et al., 2001; Bouzier-Sore et al., 2003; Chih and Roberts, 2003; Pellerin and Magistretti, 2003; Dienel and Cruz, 2004; Hertz,…”
BackgroundInfluentialBak, L. K., & Walls, A. B. (2018) · The Journal of Physiology · doi:10.1113/jp274945 · Cited by 93
“The following year, Pellerin and Magistretti (1994) published their now famed astrocyte-to-neuron lactate shuttle hypothesis in which the transfer of lactate from astrocytes to neurons, in this case derived from extracellular glucose rather than glycogen, is coupled to uptake of neurotransmitter…”
Feeding active neurons: (re)emergence of a nursing role for astrocytes
Bouzier‐Sore, A., Merle, M., Magistretti, P. J., & Pellerin, L. (2002) · Journal of Physiology-Paris · doi:10.1016/s0928-4257(02)00016-5 · Cited by 93
“consequence, Na/K ATPase activity will increase [80], leading to enhanced glucose utilization and lactate production [79], an observation that was subsequently confirmed by others [35,49,104].”
BackgroundResultInfluentialSelf-citationRegulation of neuron-astrocyte metabolic coupling across the sleep-wake cycle
Petit, J.-M., & Magistretti, P. J. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2015.12.007 · Cited by 92
“…the anatomical and biochemical properties of the astrocytes described above, Pellerin and Magistretti proposed a mechanism, by which astrocytes play the role of energy provider through the release of lactate that is used as energy substrate by glutamatergic neurons (Pellerin and Magistretti, 1994).”
BackgroundInfluentialSelf-citationMangia, S., DiNuzzo, M., Giove, F., Carruthers, A., Simpson, I. A., & Vannucci, S. J. (2011) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2011.29 · Cited by 92
“One is based on the astrocyte–neuron lactate shuttle (ANLS) hypothesis as originally proposed by Pellerin and Magistretti (1994) and subsequently modeled by Aubert and colleagues (Aubert and Costalat, 2005; Aubert et al, 2007).”
MethodNitric Oxide and Mitochondrial Function in Neurological Diseases
Ghasemi, M., Mayasi, Y. M., Hannoun, A., Eslami, S. M., & Carandang, R. A. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2018.02.017 · Cited by 93
Ocaña, M. C., Martı́nez-Poveda, B., Quesada, A. R., & Medina, M. Á. (2018) · Medicinal Research Reviews · doi:10.1002/med.21511 · Cited by 92
Contribution of the inflammasome to inflammaging
Mejias, N. H., Martinez, C. C., Stephens, M. E., & Vaccari, J. P. D. R. (2018) · Journal of Inflammation · doi:10.1186/s12950-018-0198-3 · Cited by 91
Modeling the glutamate–glutamine neurotransmitter cycle
Shen, J. (2013) · Frontiers in Neuroenergetics · doi:10.3389/fnene.2013.00001 · Cited by 92
“By extending the Magistretti hypothesis (Pellerin and Magistretti, 1994) that atroglial glycolysis is coupled to glucose oxidative in neurons Sibson et al.”
BackgroundCauses of obesity: Looking beyond the hypothalamus
Peters, A., Pellerin, L., DALLMAN, M., Oltmanns, K. M., Schweiger, U., Jan Born, A., & Fehm, H. L. (2007) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2006.12.004 · Cited by 93
Self-citationBrain alkaline intracellular pH after neonatal encephalopathy
Robertson, N. J., Cowan, F. M., Cox, I. J., & Edwards, A. D. (2002) · Annals of Neurology · doi:10.1002/ana.10365 · Cited by 92
Cellular pathways of energy metabolism in the brain: Is glucose used by neurons or astrocytes?
Nehlig, A., & Coles, J. A. (2007) · Glia · doi:10.1002/glia.20376 · Cited by 91
Rising stars: Modulation of brain functions by astroglial type‐1 cannabinoid receptors
Metna‐Laurent, M., & Marsicano, G. (2014) · Glia · doi:10.1002/glia.22773 · Cited by 100
Pharmacology and Toxicology of Astrocyte-Neuron Glutamate Transport and Cycling
Sonnewald, U., Qu, H., & Aschner, M. (2002) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.301.1.1 · Cited by 92
“Astrocytic uptake of glutamate by specific transporters has also been invoked as potentially regulating signal-transducing properties that are distinct from their transporter activity (Pellerin and Magistretti, 1994).”
BackgroundResultSibson, N. R., Shen, J., Mason, G. F., Rothman, D. L., Behar, K. L., & Shulman, R. G. (1998) · Developmental Neuroscience · doi:10.1159/000017327 · Cited by 92
Jalloh, I., Carpenter, K. L. H., Grice, P., Howe, D. J., Mason, A., Gallagher, C., Helmy, A. E., Murphy, M. P., Menon, D. K., Carpenter, T. A., et al. (2014) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2014.177 · Cited by 91
Clark, R. S. B., Carcillo, J. A., Kochanek, P. M., Obrist, W. D., Jackson, E. K., Mi, Z., Wisneiwski, S. R., Bell, M. J., & Marion, D. W. (1997) · Neurosurgery · doi:10.1097/00006123-199712000-00010 · Cited by 91
Enhanced expression of three monocarboxylate transporter isoforms in the brain of obese mice
Pierre, K., Parent, A., Jayet, P., Halestrap, A. P., Scherrer, U., & Pellerin, L. (2007) · The Journal of Physiology · doi:10.1113/jphysiol.2007.138594 · Cited by 90
“Journal compilation C© 2007 The Physiological Society Monocarboxylate transporters have been implicated in the intercellular transfer of lactate in different organs including the brain (Brooks, 1986; Pellerin & Magistretti, 1994; Gladden, 2004).”
BackgroundSelf-citationAn inverse-Warburg effect and the origin of Alzheimer’s disease
Demetrius, L., & Simon, D. K. (2012) · Biogerontology · doi:10.1007/s10522-012-9403-6 · Cited by 89
Véga, C., Martiel, J., Drouhault, D., Burckhart, M., & Coles, J. A. (2003) · The Journal of Physiology · doi:10.1113/jphysiol.2002.029751 · Cited by 90
“…that even in the presence of glucose, lactate is released by glial cells and taken up by neurons (Walz & Mukerji, 1988; Dringen et al. 1993a; Pellerin & Magistretti, 1994; Tsacopoulos & Magistretti, 1996), the most direct evidence being for the special case of the inner segments of…”
BackgroundCaloric restriction increases ketone bodies metabolism and preserves blood flow in aging brain
Lin, A.-L., Zhang, W., Gao, X., & Watts, L. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.03.012 · Cited by 90
“During intense cognitive functions, for example, astrocytic glycogenolysis is activated to provide lactate, which is transported to neurons, converted to pyruvate, and enters the TCA cycle (Brown et al., 2004; Pellerin and Magistretti, 1994).”
BackgroundAlexander disease: putative mechanisms of an astrocytic encephalopathy
Mignot, C., Boespflug‐Tanguy, O., Gélot, A., Dautigny, A., Pham-Dinh, D., & Rodriguez, D. (2004) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-003-3143-3 · Cited by 90
Global transcriptome analysis of genetically identified neurons in the adult cortex
Rossner, M. J., Hirrlinger, J., Wichert, S. P., Boehm, C., Newrzella, D., Hiemisch, H., Eisenhardt, G., Stuenkel, C., von Ahsen, O., & Nave, K.-A. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.0468-06.2006 · Cited by 89
“These in vivo observations support the existence of an astrocyte-neuron “lactate shuttle” that has recently been postulated based on cell culture data (Pellerin and Magistretti, 1994, 2004).”
BackgroundInfluentialNeuronal Death: Is There a Role for Astrocytes?
Tacconi, M. T. (1998) · Neurochemical Research · doi:10.1023/a:1022463527474 · Cited by 92
“certain neurotransmitters, like VIP, NA, adenosine and glutamate; K ions (14,33,34,35).”
BackgroundCholet, N., Pellerin, L., Welker, E., Lacombe, P. M., Seylaz, J., Magistretti, P. J., & Bonvento, G. (2001) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-200104000-00009 · Cited by 90
“, activity-dependent synaptic release of glutamate) would be neuronal (Magistretti et al., 1999; Pellerin and Magistretti, 1994).”
BackgroundInfluentialSelf-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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
