Neuron–astrocyte interactions in the regulation of brain energy metabolism: a focus on NMR spectroscopy

An adequate and timely production of ATP by brain cells is of cardinal importance to support the major energetic cost of the rapid processing of information via synaptic and action potentials. Recently, evidence has been accumulated to support the view that the regulation of brain energy metabolism is under the control of an intimate dialogue between astrocytes and neurons. In vitro studies on cultured astrocytes and in vivo studies on rodents have provided evidence that glutamate and Na+ uptake in astrocytes is a key triggering signal regulating glucose use in the brain. With the advent of NMR spectroscopy, it has been possible to provide experimental evidence to show that energy consumption is mainly devoted to glutamatergic neurotransmission and that glutamate‐glutamine cycling is coupled in a ∼ 1 : 1 molar stoichiometry to glucose oxidation, at least in the cerebral cortex. This improved understanding of neuron–astrocyte metabolic interactions offers the potential for developing novel therapeutic strategies for many neurological disorders that include a metabolic deficit.

[1]  Christian Steinhäuser,et al.  Astrocyte dysfunction in neurological disorders: a molecular perspective , 2006, Nature Reviews Neuroscience.

[2]  Albert Gjedde,et al.  Neuronal–Glial Glucose Oxidation and Glutamatergic–GABAergic Function , 2006, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[3]  Avital Schurr,et al.  Lactate: The Ultimate Cerebral Oxidative Energy Substrate? , 2006, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[4]  M. Grégoire,et al.  Glycolysis versus TCA Cycle in the Primate Brain as Measured by Combining 18F-FDG PET and 13C-NMR , 2005, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[5]  D. Attwell,et al.  Neuroenergetics and the kinetic design of excitatory synapses , 2005, Nature Reviews Neuroscience.

[6]  Gilles Bonvento,et al.  The Astrocyte—Neuron Lactate Shuttle: A Debated but still Valuable Hypothesis for Brain Imaging , 2005, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[7]  G. Bonvento,et al.  Decreased metabolic response to visual stimulation in the superior colliculus of mice lacking the glial glutamate transporter GLT‐1 , 2005, The European journal of neuroscience.

[8]  J. Meldolesi,et al.  Astrocytes, from brain glue to communication elements: the revolution continues , 2005, Nature Reviews Neuroscience.

[9]  L. Felipe Barros,et al.  Why glucose transport in the brain matters for PET , 2005, Trends in Neurosciences.

[10]  P. Magistretti,et al.  Ampakine™ CX546 bolsters energetic response of astrocytes: a novel target for cognitive‐enhancing drugs acting as α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor modulators , 2005, Journal of neurochemistry.

[11]  P. Fisher,et al.  β-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression , 2005, Nature.

[12]  Hong Yang,et al.  Glut‐1 deficiency syndrome: Clinical, genetic, and therapeutic aspects , 2005, Annals of neurology.

[13]  Luc Leybaert,et al.  Neurobarrier Coupling in the Brain: A Partner of Neurovascular and Neurometabolic Coupling? , 2005, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[14]  R. Gruetter,et al.  Neuroglial Metabolism in the Awake Rat Brain: CO2 Fixation Increases with Brain Activity , 2004, The Journal of Neuroscience.

[15]  Leif Hertz,et al.  Astrocytic control of glutamatergic activity: astrocytes as stars of the show , 2004, Trends in Neurosciences.

[16]  Leif Hertz,et al.  The Astrocyte-Neuron Lactate Shuttle: A Challenge of a Challenge , 2004, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[17]  L. Felipe Barros,et al.  Glutamate Mediates Acute Glucose Transport Inhibition in Hippocampal Neurons , 2004, The Journal of Neuroscience.

[18]  P. Magistretti,et al.  Astrocytes generate Na+-mediated metabolic waves. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[19]  R. Shulman,et al.  Glutamatergic Neurotransmission and Neuronal Glucose Oxidation are Coupled during Intense Neuronal Activation , 2004, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[20]  K. Behar,et al.  Regional glucose metabolism and glutamatergic neurotransmission in rat brain in vivo. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[21]  D. Attwell,et al.  Role of glial amino acid transporters in synaptic transmission and brain energetics , 2004, Glia.

[22]  Fahmeed Hyder,et al.  Energetic basis of brain activity: implications for neuroimaging , 2004, Trends in Neurosciences.

[23]  P. Magistretti,et al.  Dual-Gene, Dual-Cell Type Therapy against an Excitotoxic Insult by Bolstering Neuroenergetics , 2004, The Journal of Neuroscience.

[24]  Angus M. Brown Brain glycogen re‐awakened , 2004, Journal of neurochemistry.

[25]  B. McEwen,et al.  Glucose transporter expression in the central nervous system: relationship to synaptic function. , 2004, European journal of pharmacology.

[26]  J. Rothstein,et al.  Glutamate transporters: animal models to neurologic disease , 2004, Neurobiology of Disease.

[27]  A. Nehlig Brain uptake and metabolism of ketone bodies in animal models. , 2004, Prostaglandins, leukotrienes, and essential fatty acids.

[28]  R. Fremeau,et al.  VGLUTs define subsets of excitatory neurons and suggest novel roles for glutamate , 2004, Trends in Neurosciences.

[29]  B. Mackenzie,et al.  Sodium-coupled neutral amino acid (System N/A) transporters of the SLC38 gene family , 2004, Pflügers Archiv.

[30]  Pierre J Magistretti,et al.  Lactate is a Preferential Oxidative Energy Substrate over Glucose for Neurons in Culture , 2003, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[31]  Gilles Bonvento,et al.  Glial glutamate transporters and maturation of the mouse somatosensory cortex. , 2003, Cerebral cortex.

[32]  D. Leibfritz,et al.  Regulation of glial metabolism studied by 13C‐NMR , 2003, NMR in biomedicine.

[33]  S. Serres,et al.  Involvement of brain lactate in neuronal metabolism , 2003, NMR in biomedicine.

[34]  Eng H. Lo,et al.  Neurological diseases: Mechanisms, challenges and opportunities in stroke , 2003, Nature Reviews Neuroscience.

[35]  E. Welker,et al.  Glial Glutamate Transporters Mediate a Functional Metabolic Crosstalk between Neurons and Astrocytes in the Mouse Developing Cortex , 2003, Neuron.

[36]  A. Schousboe,et al.  Demonstration of Pyruvate Recycling in Primary Cultures of Neocortical Astrocytes but Not in Neurons , 2002, Neurochemical Research.

[37]  R. Gruetter,et al.  Effect of Deep Pentobarbital Anesthesia on Neurotransmitter Metabolism in Vivo: On the Correlation of Total Glucose Consumption with Glutamatergic Action , 2002, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[38]  R. Gruetter In vivo 13 C NMR studies of compartmentalized cerebral carbohydrate metabolism , 2002, Neurochemistry International.

[39]  K. Petersen,et al.  Astroglial Contribution to Brain Energy Metabolism in Humans Revealed by 13C Nuclear Magnetic Resonance Spectroscopy: Elucidation of the Dominant Pathway for Neurotransmitter Glutamate Repletion and Measurement of Astrocytic Oxidative Metabolism , 2002, The Journal of Neuroscience.

[40]  I. Macdonald,et al.  Measurement of human tricarboxylic acid cycle rates during visual activation by 13C magnetic resonance spectroscopy , 2001, Journal of neuroscience research.

[41]  S. Laughlin,et al.  An Energy Budget for Signaling in the Grey Matter of the Brain , 2001, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[42]  M. Raichle,et al.  Searching for a baseline: Functional imaging and the resting human brain , 2001, Nature Reviews Neuroscience.

[43]  N. Danbolt Glutamate uptake , 2001, Progress in Neurobiology.

[44]  K. Uğurbil,et al.  A mathematical model of compartmentalized neurotransmitter metabolism in the human brain. , 2001, American journal of physiology. Endocrinology and metabolism.

[45]  K. Uğurbil,et al.  Study of tricarboxylic acid cycle flux changes in human visual cortex during hemifield visual stimulation using 1H‐{13C} MRS and fMRI , 2001, Magnetic resonance in medicine.

[46]  R. Shulman,et al.  In vivo13C NMR measurement of neurotransmitter glutamate cycling, anaplerosis and TCA cycle flux in rat brain during [2‐13C]glucose infusion , 2001, Journal of neurochemistry.

[47]  D. Leibfritz,et al.  NMR spectroscopic study on the metabolic fate of [3‐13C]alanine in astrocytes, neurons, and cocultures: Implications for glia‐neuron interactions in neurotransmitter metabolism , 2000, Glia.

[48]  Adelbert Ames,et al.  CNS energy metabolism as related to function , 2000, Brain Research Reviews.

[49]  P. Marquet,et al.  A quantitative analysis of l‐glutamate‐regulated Na+ dynamics in mouse cortical astrocytes: implications for cellular bioenergetics , 2000, The European journal of neuroscience.

[50]  A. Schousboe,et al.  A Possible Role of Alanine for Ammonia Transfer Between Astrocytes and Glutamatergic Neurons , 2000, Journal of neurochemistry.

[51]  M. Beal Energetics in the pathogenesis of neurodegenerative diseases , 2000, Trends in Neurosciences.

[52]  B. Gähwiler,et al.  Acute decrease in net glutamate uptake during energy deprivation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[53]  A. Schousboe,et al.  Compartmentation of TCA cycle metabolism in cultured neocortical neurons revealed by 13C MR spectroscopy , 2000, Neurochemistry International.

[54]  D. Attwell,et al.  Glutamate release in severe brain ischaemia is mainly by reversed uptake , 2000, Nature.

[55]  Rolf Gruetter,et al.  Noninvasive Measurements of [1‐13C] Glycogen Concentrations and Metabolism in Rat Brain In Vivo , 1999, Journal of neurochemistry.

[56]  P. Honegger,et al.  Separate Neuronal and Glial Na+,K+-ATPase Isoforms Regulate Glucose Utilization in Response to Membrane Depolarization and Elevated Extracellular Potassium , 1999, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[57]  R. Shulman,et al.  Determination of the rate of the glutamate/glutamine cycle in the human brain by in vivo 13C NMR. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[58]  L. Sokoloff Energetics of Functional Activation in Neural Tissues , 1999, Neurochemical Research.

[59]  M. Raichle Behind the scenes of functional brain imaging: a historical and physiological perspective. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[60]  R. Shulman,et al.  Stoichiometric coupling of brain glucose metabolism and glutamatergic neuronal activity. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[61]  K. Nagata [Brain energy metabolism]. , 1997, Nihon rinsho. Japanese journal of clinical medicine.

[62]  S. Vannucci,et al.  Glucose transporter proteins in brain: Delivery of glucose to neurons and glia , 1997, Glia.

[63]  R G Shulman,et al.  In vivo 13C NMR measurements of cerebral glutamine synthesis as evidence for glutamate-glutamine cycling. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[64]  Christian Giaume,et al.  Control of gap-junctional communication in astrocytic networks , 1996, Trends in Neurosciences.

[65]  F. Hyder,et al.  Increased tricarboxylic acid cycle flux in rat brain during forepaw stimulation detected with 1H[13C]NMR. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[66]  A. Levey,et al.  Selective loss of glial glutamate transporter GLT‐1 in amyotrophic lateral sclerosis , 1995, Annals of neurology.

[67]  L. Sokoloff,et al.  Role of sodium and potassium ions in regulation of glucose metabolism in cultured astroglia. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[68]  P. Magistretti,et al.  Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[69]  Rolf Gruetter,et al.  Localized 13C NMR Spectroscopy in the Human Brain of Amino Acid Labeling from d‐[1‐13C]Glucose , 1994, Journal of neurochemistry.

[70]  J. Rothstein,et al.  Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. , 1992, The New England journal of medicine.

[71]  D. Tank,et al.  Brain magnetic resonance imaging with contrast dependent on blood oxygenation. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[72]  M. Mintun,et al.  Nonoxidative glucose consumption during focal physiologic neural activity. , 1988, Science.

[73]  R. Shulman,et al.  Detection of metabolites in rabbit brain by 13C NMR spectroscopy following administration of [1‐13C]glucose , 1986, Magnetic resonance in medicine.

[74]  P. Yarowsky,et al.  Effect of monensin on deoxyglucose uptake in cultured astrocytes: energy metabolism is coupled to sodium entry , 1986, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[75]  M. Raichle,et al.  Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[76]  R G Shulman,et al.  1H-Observe/13C-decouple spectroscopic measurements of lactate and glutamate in the rat brain in vivo. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[77]  INTERNATIONAL SOCIETY FOR NEUROCHEMISTRY , 1976 .

[78]  R. Webster Magnetic Resonance Spectroscopy , 1962, Nature.

[79]  J. Franconi,et al.  Ex vivo NMR study of lactate metabolism in rat brain under various depressed states , 2005, Journal of neuroscience research.

[80]  C. Henderson,et al.  Role of WHO. , 1982, Experientia. Supplementum.

[81]  B. Siesjö,et al.  Brain energy metabolism , 1978 .

[82]  N. Dubin Mathematical Model , 2022 .