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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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“However, this model is criticized by at least the following points, namely, (i) the ANLS is inconsistent with the existing data on stoichiometry of brain metabolism and with the rapid excretion of L-lactate after neuronal activity [17] and (ii) the capacity of neuronal glucose uptake and oxidative metabolism is large…”
BackgroundInfluentialC9orf72 expansion within astrocytes reduces metabolic flexibility in amyotrophic lateral sclerosis
Allen, S. P., Hall, B., Woof, R., Francis, L. I., Gatto, N., Shaw, A. C., Myszczynska, M. A., Hemingway, J., Coldicott, I., Willcock, A., et al. (2019) · Brain · doi:10.1093/brain/awz302 · Cited by 89
Energy Metabolism in the Inner Retina in Health and Glaucoma
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“They provided evidence that uptake of glutamate by astrocytes results in the activation of the Na+/K+ ATPase, which triggers glucose uptake and its glycolytic processing [200].”
BackgroundFila, M., Chojnacki, C. J., Chojnacki, J., & Błasiak, J. (2021) · Nutrients · doi:10.3390/nu13124433 · Cited by 95
“glutamate released by neurons into synapses was taken by astrocytes, in which glutamate stimulated glycolysis and the production of lactate, which can be oxidized in neurons [27].”
BackgroundKreft, M., Bak, L. K., Waagepetersen, H. S., & Schousboe, A. (2012) · ASN Neuro · doi:10.1042/an20120007 · Cited by 88
“In astrocytes, noradrenaline activates both a- and b- adrenergic receptors (Northam et al., 1989; Hertz et al., 2010), which induces glycogen breakdown (Subbarao and Hertz, 1990a, 1991; Pellerin and Magistretti, 1994; Fray et al., 1996; Gibbs et al., 2008; Walls et al., 2009; Obel et al., 2012).”
BackgroundInfluentialDeciphering neuron-glia compartmentalization in cortical energy metabolism
Jolivet, R. (2009) · Frontiers in Neuroenergetics · doi:10.3389/neuro.14.004.2009 · Cited by 89
“The fi ndings presented here are also consistent with an activityregulated transfer of glucose-derived metabolites from astrocytes to neurons as it was originally proposed by Pellerin and Magistretti (1994).”
InfluentialCopelman, C. A., Cuzner, M. L., Groome, N. P., & Diemel, L. T. (2000) · Glia · doi:10.1002/(sici)1098-1136(200006)30:4 · Cited by 35
Self-citationZwingmann, C., Richter‐Landsberg, C., & Leibfritz, D. (2001) · Glia · doi:10.1002/glia.1054 · Cited by 89
Lactate topography of the human brain using hyperpolarized 13C-MRI
Lee, C. Y., Soliman, H., Geraghty, B. J., Chen, A. P., Connelly, K. A., Endre, R., Perks, W. J., Heyn, C., Black, S. E., & Cunningham, C. H. (2019) · NeuroImage · doi:10.1016/j.neuroimage.2019.116202 · Cited by 88
Can the emerging field of immunometabolism provide insights into neuroinflammation?
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Advanced monitoring in the neurology intensive care unit: microdialysis
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Magistretti, P. J., & Chatton, J. (2004) · Journal of Neural Transmission · doi:10.1007/s00702-004-0171-6 · Cited by 88
“The link between glutamate transport and certain metabolic responses has been documented (Chatton et al., 2000; Pellerin and Magistretti, 1994) and is supported by evidence indicating that the Naþ load associated with glutamate transport causes an activation of the Naþ=Kþ-ATPase thus increasing the…”
InfluentialPyruvate and lactate protect striatal neurons against N‐methyl‐ d ‐aspartate‐induced neurotoxicity
Maus, M., Marin, P., Israël, M., Glowinski, J., & Prémont, J. (1999) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.1999.00745.x · Cited by 88
“In addition, the release of lactate from glial cells is enhanced by glutamate which stimulates the glycolytic processing of glucose in these cells (Pellerin & Magistretti, 1994).”
BackgroundLactate Shuttling and Lactate use as Fuel after Traumatic Brain Injury: Metabolic Considerations
Dienel, G. A. (2014) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2014.153 · Cited by 85
Prion Protein Regulates Glutamate-Dependent Lactate Transport of Astrocytes
KLEENE, R. B., Loers, G., Langer, J., Frobert, Y., Buck, F., & Schachner, M. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.1358-07.2007 · Cited by 88
“, in the presence of the excitatory neurotransmitter glutamate) (Pellerin and Magistretti, 1994; Pellerin et al., 1998).”
BackgroundWagner, K. R., Xi, G., Hua, Y., Kleinholz, M., de Courten‐Myers, G. M., & Myers, R. E. (1998) · Journal of neurosurgery · doi:10.3171/jns.1998.88.6.1058 · Cited by 88
Astrocyte activation in working brain: Energy supplied by minor substrates
Dienel, G. A., & Cruz, N. F. (2006) · Neurochemistry International · doi:10.1016/j.neuint.2006.01.004 · Cited by 87
Chowdhury, G. M. I., Patel, A. B., Mason, G. F., Rothman, D. L., & Behar, K. L. (2007) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600490 · Cited by 87
“Studies of cultured astroglia by Magistretti and coworkers (Pellerin and Magistretti, 1994) have shown that uptake of glutamate with co-transported sodium stimulates glial glucose utilization and the release of lactate.”
BackgroundThe role of lactate in brain metabolism
Fillenz, M. (2005) · Neurochemistry International · doi:10.1016/j.neuint.2005.05.011 · Cited by 88
Çakır, T., Alsan, S., Saybaşılı, H., Akın, A., & Ülgen, K. Ö. (2007) · Theoretical Biology and Medical Modelling · doi:10.1186/1742-4682-4-48 · Cited by 89
How to balance the brain energy budget while spending glucose differently
Pellerin, L., & Magistretti, P. J. (2003) · The Journal of Physiology · doi:10.1113/jphysiol.2002.035105 · Cited by 87
“Thus, it was postulated that in the central nervous system, astrocytes could respond to increased synaptic activity via glutamate uptake by increasing their rate of aerobic glycolysis, i.e. glucose consumption and lactate production (Pellerin & Magistretti 1994).”
BackgroundSelf-citationRevisiting enigmatic cortical calretinin-expressing interneurons
Cauli, B., Zhou, X., Tricoire, L., Toussay, X., & Staiger, J. F. (2014) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2014.00052 · Cited by 86
Age-dependent metabolic dysregulation in cancer and Alzheimer’s disease
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Pellerin, L. (2010) · Diabetes & Metabolism · doi:10.1016/s1262-3636(10)70469-9 · Cited by 86
Self-citationSatellite Glial Cells and Astrocytes, a Comparative Review
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“, 2015) which were interpretable in terms of inflammation causing an increase in astrocyte-neuronal lactate shuttling and aerobic glycolysis (Pellerin and Magistretti, 1994).”
BackgroundEndocannabinoid signaling in astrocytes
Eraso‐Pichot, A., Pouvreau, S., Oliveira-Pinto, A., Gómez-Sotres, P., Skupio, U., & Marsicano, G. (2022) · Glia · doi:10.1002/glia.24246 · Cited by 89
“The ANLS claims that astrocytes are capa- ble to perform aerobic glycolysis and release lactate that will be in turn used by neighboring neurons as a metabolic or signaling mole- cule (Barros, 2013; Bélanger et al., 2011; Pellerin & Magistretti, 1994).”
BackgroundSala, N., Suys, T., Zerlauth, J.-B., Bouzat, P., Messerer, M., Bloch, J., Levivier, M., Magistretti, P. J., Meuli, R. A., & Oddo, M. (2013) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2013.142 · Cited by 86
Dopamine increases glial cell line-derived neurotrophic factor in human fetal astrocytes
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Stimulated release of lactate in freely moving rats is dependent on the uptake of glutamate.
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Rapid Efflux of Lactate from Cerebral Cortex during K + -Induced Spreading Cortical Depression
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NH4+ triggers the release of astrocytic lactate via mitochondrial pyruvate shunting
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“Aerobic glycolysis may be triggered by stimulation of astrocytic glycolysis, such as that observed in response to glutamate or to high K (11, 12).”
BackgroundInfluentialHüppi, P. S., & Inder, T. E. (2001) · Seminars in Neonatology · doi:10.1053/siny.2001.0039 · Cited by 84
Rosafio, K., & Pellerin, L. (2013) · Glia · doi:10.1002/glia.22618 · Cited by 85
Self-citationMetabolic Contribution and Cerebral Blood Flow Regulation by Astrocytes in the Neurovascular Unit
Takahashi, S. (2022) · Cells · doi:10.3390/cells11050813 · Cited by 91
“Pellerin and Magistretti [75] observed that glutamate loading of cultured astrocytes resulted in increased glucose consumption and increased lactate release from astrocytes, reflecting a transient increase in glycolytic activity during in vivo”
BackgroundResultGlutamate transporters in brain ischemia: to modulate or not?
Krzyżanowska, W., Pomierny, B., Filip, M., & Pera, J. (2014) · Acta Pharmacologica Sinica · doi:10.1038/aps.2014.1 · Cited by 86
Dutta, A., Jacob, A. J., Chowdhury, S. R., Das, A., & Nitsche, M. A. (2015) · Journal of Medical Systems · doi:10.1007/s10916-015-0205-7 · Cited by 85
“For example, depolarization of presynaptic glutamate terminals can increase the probability of glutamate release, and glutamate uptake into astrocytes may stimulate aerobic glycolysis - a mechanism coupling neuronal activity to glucose utilization [16].”
BackgroundShould We Stop Saying ‘Glia’ and ‘Neuroinflammation’?
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Jeon, H., Kim, M., Park, W., Lim, J. S., Lee, E., Cha, H., Ahn, J. S., Kim, J. H., Hong, S. H., Park, J. E., et al. (2021) · Neurotherapeutics · doi:10.1007/s13311-021-01126-2 · Cited by 90
In vivo methods for imaging blood–brain barrier function and dysfunction
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Coupling between neuronal activity and microcirculation: Implications for functional brain imaging
Vanzetta, I., & Grinvald, A. (2008) · HFSP journal · doi:10.2976/1.2889618 · Cited by 87
“, Hu and Wilson, 1997), the controversy regarding these issues is not yet resolved (Chih and Roberts Jr, 2003; Pellerin and Magistretti, 1994; for a review, see Schurr, 2006).”
BackgroundInfluentialRegulation of blood flow in activated human brain by cytosolic NADH/NAD + ratio
Vlassenko, A. G., Rundle, M. M., Raichle, M. E., & Mintun, M. A. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510632103 · Cited by 84
McKenna, M. C. (2012) · Neurochemical Research · doi:10.1007/s11064-012-0901-3 · Cited by 84
“Glutamate uptake by astrocytes stimulates glycolysis in some astrocyte preparations [83, 84], but this is not a universal finding because glutamate exposure does not stimulate glycolysis in all astrocyte preparations [85].”
BackgroundPfund, Z., Chugani, D. C., Juhász, C., Muzik, O., Chugani, H. T., Wilds, I. B., Seraji‐Bozorgzad, N., & Moore, G. J. (2000) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-200005000-00014 · Cited by 84
Duarte, J. M. N., Lanz, B., & Gruetter, R. (2011) · Frontiers in Neuroenergetics · doi:10.3389/fnene.2011.00003 · Cited by 82
“The produced lactate is transferred to neurons for oxidative degradation (Pellerin and Magistretti, 1994; Magistretti et al., 1999).”
BackgroundEarly effects of LPS-induced neuroinflammation on the rat hippocampal glycolytic pathway
Vizuete, A. F. K., Fróes, F. T., Seady, M., Zanotto, C., Bobermin, L. D., Roginski, A. C., Wajner, M., Quincozes‐Santos, A., & Gonçalves, C. A. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02612-w · Cited by 88
“It is known that glutamate uptake by astrocytes is mediated by a Na+ dependent gradient [43] and associated with higher glucose consumption [31, 44].”
BackgroundMethodAstrocyte-neuron circuits in epilepsy
Purnell, B. S., Alves, M., & Boison, D. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106058 · Cited by 83
“This energy transfer process is enabled by an astrocyte-to-neuron lactate shuttle (Pellerin and Magistretti, 1994).”
Zwingmann, C., & Butterworth, R. F. (2005) · Neurochemistry International · doi:10.1016/j.neuint.2005.04.003 · Cited by 83
In vivo 13C NMR assessment of brain glycogen concentration and turnover in the awake rat
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MCT Expression and Lactate Influx/Efflux in Tanycytes Involved in Glia-Neuron Metabolic Interaction
Cortés‐Campos, C., Elizondo-Vega, R. J., Llanos, P., Uranga, R. M., Nualart, F., & García, M. D. L. Á. (2011) · PLoS ONE · doi:10.1371/journal.pone.0016411 · Cited by 87
“Physiological concentration of glucose induced lactate efflux in cultured tanycytes, which was similar to the lactate efflux reported in astrocytes exposed to glutamate [45].”
ResultCellular Links between Neuronal Activity and Energy Homeostasis
Shetty, P. K., Galeffi, F., & Turner, D. A. (2012) · Frontiers in Pharmacology · doi:10.3389/fphar.2012.00043 · Cited by 81
“Glycogen-derived lactate is likely released into the ECS (Figure 3) and taken up by neurons for energy, particularly in low glucose conditions where glycogenolysis is initiated (Dringen et al., 1993; Pellerin and Magistretti, 1994; Magistretti and Pellerin, 1999; Brown et al., 2004).”
BackgroundHertz, L., & Rothman, D. L. (2017) · Biology · doi:10.3390/biology6010017 · Cited by 87
“A caveat is that the cells used by these authors, like those used by Pellerin and Magistretti [88], were unable to derive energy by glutamate oxidation.”
MethodMascarucci, P., Perego, C., Terrazzino, S., & Simoni, M. G. D. (1998) · Neuroscience · doi:10.1016/s0306-4522(98)00105-5 · Cited by 83
Vaucher, E., Linville, D. G., & Hamel, É. (1997) · Neuroscience · doi:10.1016/s0306-4522(97)00033-x · Cited by 83
“as possible intermediates in the neurogenic control of brain microcirculation(9,22) and local metabolic activation.(41) It is thus conceivable that NO from astrocytic endfeet could diffuse to adjacent cerebral vessels and modulate their function.”
The Oxygen Paradox, the French Paradox, and age-related diseases
Davies, J. M. S., Cillard, J., Friguet, B., Cadenas, E., Cadet, J., Cayce, R., Fishmann, A., Liao, D., Bulteau, A.-L., Derbré, F., et al. (2017) · GeroScience · doi:10.1007/s11357-017-0002-y · Cited by 82
“and (iii) lactate is shuttled from astrocytes to neurons via monocarboxylate transporters (MCTs) where it is converted back to pyruvate and enters the TCA cycle in mitochondria (Pellerin and Magistretti 1994).”
BackgroundElectrodiffusive Model for Astrocytic and Neuronal Ion Concentration Dynamics
Halnes, G., Østby, I., Pettersen, K. H., Omholt, S. W., & Einevoll, G. T. (2013) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003386 · Cited by 82
“Astrocytes (a species of glial cells) play an important role in modulating excitatory and inhibitory synapses by removal, metabolism, and release of neurotransmitters [4], homeostatic maintenance of extracellular K, H, and glutamate [5], supply of energy substrates for neurons [6], and neuronal pathfinding during deve…”
BackgroundCharacterization of Adult Rat Astrocyte Cultures
Souza, D. G., Bellaver, B., Souza, D. O., & Quincozes-Santos, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0060282 · Cited by 82
“Classically, glutamate stimulates glucose uptake in astrocytes [35].”
BackgroundMethodInfluentialLactate Supply from Astrocytes to Neurons and its Role in Ischemic Stroke-induced Neurodegeneration
Yamagata, K. (2021) · Neuroscience · doi:10.1016/j.neuroscience.2021.11.035 · Cited by 82
Wilson, C. L., Natarajan, V., Hayward, S. L., Khalimonchuk, O., & Kidambi, S. (2015) · Nanoscale · doi:10.1039/c5nr03646a · Cited by 80
Traumatic brain injury in infants and children
Bayır, H., Kochanek, P. M., & Clark, R. S. B. (2003) · Critical Care Clinics · doi:10.1016/s0749-0704(03)00014-9 · Cited by 82
“Glutamate uptake, acidosis, and arachidonic acid have been shown to contribute to astrocyte swelling [90–92].”
BackgroundMitochondrial Metabolism-Mediated Regulation of Adult Neurogenesis
Beckervordersandforth, R. (2017) · Brain Plasticity · doi:10.3233/bpl-170044 · Cited by 82
Lactate transporters as therapeutic targets in cancer and inflammatory diseases
Pucino, V., Cucchi, D., & Mauro, C. (2018) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2018.1511706 · Cited by 87
“glutamate released in the synapse triggers glucose uptake and therefore lactate production by astrocytes; lactate is then utilized by neurons as a source of energy [29].”
BackgroundAblation of reactive astrocytes exacerbates disease pathology in a model of Alzheimer's disease
Katsouri, L., Birch, A. M., Renziehausen, A. W. J., Zach, C., Aman, Y., Steeds, H., Bonsu, A., Palmer, E. O. C., Mirzaei, N., Ries, M., et al. (2020) · Glia · doi:10.1002/glia.23759 · Cited by 81
“Furthermore, astrocytes provide trophic support to neurons (Pellerin & Magistretti, 1994), are involved in neurotransmitter uptake and recycling (Rothstein et al., 1996), and interact directly with synapses (Osborn, Kamphuis,Loukia Katsouri and Amy M. Birch contributed equally to this study.”
BackgroundLactate Transporters Mediate Glia-Neuron Metabolic Crosstalk in Homeostasis and Disease
Jha, M. K., & Morrison, B. M. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.589582 · Cited by 81
Na+‐Ca2+ cosignaling in the stimulation of the glucose transporter GLUT1 in cultured astrocytes
Porras, O. H., Ruminot, I., Loaiza, A., & Barros, L. F. (2007) · Glia · doi:10.1002/glia.20589 · Cited by 81
“The participation of the cascade glutamate/Na1-glutamate cotransporter/ Na1-K1 ATPase pump in both glucose transport stimulation (this work) and glycolytic stimulation (Pellerin and Magistretti, 1994, 1997; Voutsinos-Porche et al., 2003), is one way in which coordination may be achieved.”
BackgroundGsell, W., Burke, M., Wiedermann, D., Bonvento, G., Silva, A. C., Dauphin, F., Bührle, C., Hoehn, M., & Schwindt, W. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.4615-05.2006 · Cited by 81
“The metabolic response, on the one hand, is probably mediated by glial transport of glutamate and its recycling through mechanisms involving changes in intracellular Na concentration (Pellerin and Magistretti, 1994; Chatton et al., 2000; Bernardinelli et al., 2004).”
BackgroundBaron, J., & Jones, T. (2011) · NeuroImage · doi:10.1016/j.neuroimage.2011.12.036 · Cited by 81
“Although these observations contradicted then prevailing concepts, it was taken forward by Pellerin and Magistretti, who showed the biochemical underpinning of this flow-oxygen uncoupling (Pellerin and Magistretti, 1994).”
O’Brien, J., Kla, K. M., Hopkins, I. B., Malecki, E. A., & McKenna, M. C. (2006) · Neurochemical Research · doi:10.1007/s11064-006-9132-9 · Cited by 81
“The astrocyte-to-neuron lactate shuttle (ANLSH) proposed by Magistretti and Pellerin links neurotransmitter glutamate-stimulated lactate release from astrocytes to uptake and use of lactate by neurons [ 17 , 18, 61, 62].”
BackgroundValbuena, G. N., Rizzardini, M., Cimini, S., Siskos, A., Bendotti, C., Cantoni, L., & Keun, H. C. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9165-7 · Cited by 80
“cytes, glutamate uptake is coupled with a shift in glycolysis towards lactate production [53] while in neurons, increasing lactate uptake through increased monocarboxylate transporter”
Norepinephrine stimulates glycogenolysis in astrocytes to fuel neurons with lactate
Coggan, J. S., Keller, D. X., Calì, C., Lehväslaiho, H., Markram, H., Schürmann, F., & Magistretti, P. J. (2018) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1006392 · Cited by 79
“We built on our previous computational model of ANLS to explore the dynamics of glycogen mobilization by NE release from LC terminals and test whether existing knowledge of the enzymatic cascades supports the role of glycogen as a source of energy both to astrocytes and neurons.”
BackgroundInfluentialBouzat, P., & Oddo, M. (2014) · Current Opinion in Critical Care · doi:10.1097/mcc.0000000000000072 · Cited by 81
“According to the astrocyte–neuron lactate shuttle model [21], increase of glutamate upon neuronal activation triggers Naþ/Kþ-ATPase, which in turn activates astrocytic glycolysis with subsequent lactate production and release in the extracellular space.”
BackgroundNetzahualcoyotzi, C., & Pellerin, L. (2020) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2020.101888 · Cited by 85
Self-citationA Metabolic Landscape for Maintaining Retina Integrity and Function
Viegas, F., & Neuhauss, S. C. F. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.656000 · Cited by 81
Lactate and Lactylation in the Brain: Current Progress and Perspectives
Li, R., Yang, Y., Wang, H., Zhang, T., Duan, F., Wu, K., Yang, S., Xu, K., Jiang, X., & Sun, X. (2023) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-023-01335-7 · Cited by 82
“2016), a concept known as the astrocyte–neuron lactate shuttle hypothesis (Pellerin and Magistretti 1994), which was proposed to shift the stereotype of lactate as a metabolic waste product and emphasize the critical function of lactate in brain metabolism.”
BackgroundElevated blood lactate is associated with increased motor cortex excitability
Coco, M., Alagona, G., Rapisarda, G., Costanzo, E., Calogero, R. A., Perciavalle, V., & Perciavalle, V. (2010) · Somatosensory & Motor Research · doi:10.3109/08990220903471765 · Cited by 76
Cerebral glycolysis: a century of persistent misunderstanding and misconception
Schurr, A. (2014) · Frontiers in Neuroscience · doi:10.3389/fnins.2014.00360 · Cited by 90
“…in oxidative energy metabolism, both in muscle (Brooks, 1998, 2000, 2002a,b; Brooks et al., 1999a,b) and especially in brain (Izumi et al., 1994; Pellerin and Magistretti, 1994, 2003; Larrabee, 1995, 1996; Tsacopoulos and Magistretti, 1996; Hu and Wilson, 1997a,b; Schurr et al., 1997a, 1999a,b;…”
BackgroundAstrocyte sodium signaling and the regulation of neurotransmission
Kirischuk, S., Héja, L., Kardos, J., & Billups, B. (2015) · Glia · doi:10.1002/glia.22943 · Cited by 82
Biophysical basis of brain activity: implications for neuroimaging
Shulman, R. G., Hyder, F., & Rothman, D. L. (2002) · Quarterly Reviews of Biophysics · doi:10.1017/s0033583502003803 · Cited by 79
An astrocyte bridge from synapse to blood flow
Parri, H. R., & Crunelli, V. (2002) · Nature Neuroscience · doi:10.1038/nn0103-5 · Cited by 79
Brain energetics (thought needs food)
Pellerin, L. (2008) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0b013e328312c368 · Cited by 79
Self-citationMason, G. F., Petersen, K. F., de Graaf, R. A., Kanamatsu, T., Otsuki, T., & Rothman, D. L. (2003) · Brain Research Protocols · doi:10.1016/s1385-299x(02)00217-9 · Cited by 79
Chan, B. S., Endo, S., KANAI, N., & Schuster, V. L. (2002) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00151.2001 · Cited by 79
“Lactate production under aerobic conditions has been described in many tissues, including lung (28, 32, 40, 47), kidney (38, 60), brain (36, 42), vascular smooth muscle (5, 35, 41), heart (2, 20), and skeletal muscle (11, 23).”
BackgroundHarris, J. L., Choi, I.-Y., & Brooks, W. M. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00202 · Cited by 78
“According to the lactate shuttle hypothesis, glycolysis in astrocytes generates lactate (Lac), which is then released from the astrocytes to serve as a preferred fuel for neurons (Pellerin and Magistretti, 1994).”
BackgroundEffects of Normobaric Hyperoxia in Traumatic Brain Injury: A Randomized Controlled Clinical Trial
Taher, A., Pilehvari, Z., Poorolajal, J., & Aghajanloo, M. (2016) · Trauma Monthly · doi:10.5812/traumamon.26772 · Cited by 77
“Due to an increased rate of ion transportation after neuron injury, there is an increased need for glucose, which is usually supplied through glycogenolysis in astrocytes (7).”
BackgroundMurphy‐Royal, C., Gordon, G. R., & Bains, J. S. (2019) · Glia · doi:10.1002/glia.23610 · Cited by 80
“The idea that astrocytes support neuronal activity with lactate in an activity-dependent manner was originally proposed by Pellerin and Magistretti (1994), and forms the basis of what is now known as the astrocyte-neuron lactate shuttle (ANLS) hypothesis (Magistretti & Allaman, 2018).”
Vezzoli, E., Calì, C., De Roo, M., Ponzoni, L., Sogne, E., Gagnon, N., Francolini, M., Braida, D., Sala, M., Muller, D., et al. (2020) · Cerebral Cortex · doi:10.1093/cercor/bhz226 · Cited by 79
“Such lactate is then transferred to neurons through specific monocarboxylate transporters (MCT) via a process known as the astrocyte–neuron lactate shuttle (ANLS) (Pellerin and Magistretti 1994, Magistretti and Allaman 2015; Magistretti and Allaman 2018; Calì et al. 2019).”
InfluentialMetabolic regulation of neurodifferentiation in the adult brain
Maffezzini, C., Calvo‐Garrido, J., Wredenberg, A., & Freyer, C. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03430-9 · Cited by 86
Velebit, J., Horvat, A., Smolič, T., Mihevc, S. P., Rogelj, B., Zorec, R., & Vardjan, N. (2020) · Scientific Reports · doi:10.1038/s41598-020-62864-5 · Cited by 82
Allaman, I., Pellerin, L., & Magistretti, P. J. (2004) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.02235.x · Cited by 78
Self-citationGlutamate Controls tPA Recycling by Astrocytes, Which in Turn Influences Glutamatergic Signals
Cassé, F., Bardou, I., Danglot, L., Briens, A., Montagne, A., Parcq, J., Alahari, A., Galli, T., Vivien, D., & Docagne, F. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.5296-11.2012 · Cited by 78
“This mechanism is reminiscent of the classical neuron–astrocyte coupling in which glutamate, released during synaptic transmission, is taken up by astrocytes and converted to glutamine before being transported back to neurons and recycled into glutamate (Pellerin and Magistretti, 1994).”
BackgroundInfluentialGarcia-Espinosa, M. A., Wallin, R., Hutson, S. M., & Sweatt, A. J. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04332.x · Cited by 78
Hounoum, B. M., Mavel, S., Coque, E., Patin, F., Vourc’h, P., Marouillat, S., Nadal‐Desbarats, L., Emond, P., Corcia, P., Andres, C. R., et al. (2017) · Glia · doi:10.1002/glia.23114 · Cited by 83
Glutamate, a neurotransmitter—And so much more
Hertz, L. (2006) · Neurochemistry International · doi:10.1016/j.neuint.2005.12.021 · Cited by 78
Myelin and disorders that affect the formation and maintenance of this sheath
Porter, B. E., & Tennekoon, G. I. (2000) · Mental Retardation and Developmental Disabilities Research Reviews · doi:10.1002/(sici)1098-2779(2000)6:1 · Cited by 14
Ischaemia triggered by spreading neuronal activation is inhibited by vasodilators in rats
Dreier, J. P., Petzold, G. C., Tille, K., Lindauer, U., Arnold, G., Heinemann, U., Einhäupl, K. M., & Dirnagl, U. (2001) · The Journal of Physiology · doi:10.1111/j.1469-7793.2001.0515i.x · Cited by 78
“Interactions between neurones and astrocytes during neuronal activation are also assumed at the level of neuronal nutrition (neurometabolic coupling) (Pellerin & Magistretti, 1994).”
BackgroundLigneul, C., Palombo, M., Hernández-Garzón, E., Carrillo-de Sauvage, M.-A., Flament, J., Hantraye, P., Brouillet, E., Bonvento, G., Escartin, C., & Valette, J. (2019) · NeuroImage · doi:10.1016/j.neuroimage.2019.02.046 · Cited by 77
“This would open unprecedented possibilities to study lactate metabolism and astrocyte-neuron interactions in various contexts, such as brain activity (Pellerin and Magistretti, 1994), synaptic plasticity and long-term memory (Suzuki et al.”
BackgroundResultActivated astrocytes: a therapeutic target in Alzheimer’s disease?
Fuller, S. L., Münch, G. W., & Steele, M. L. (2009) · Expert Review of Neurotherapeutics · doi:10.1586/ern.09.111 · Cited by 77
Glial glucose fuels the neuronal pentose phosphate pathway for long-term memory
de Tredern, É., Rabah, Y., Pasquer, L., Minatchy, J., Plaçais, P.-Y., & Préat, T. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109620 · Cited by 79
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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