Molecular Neurobiology

, Volume 32, Issue 1, pp 59–72

How astrocytes feed hungry neurons

Article

Abstract

For years glucose was thought to constitute the sole energy substrate for neurons; it was believed to be directly provided to neurons via the extracellular space by the cerebral circulation. It was recently proposed that in addition to glucose, neurons might rely on lactate to sustain their activity. Therefore, it was demonstrated that lactate is a preferred oxidative substrate for neurons not only in vitro but also in vivo. Moreover, the presence of specific monocarboxylate transporters on neurons as well as on astrocytes is consistent with the hypothesis of a transfer of lactate from astrocytes to neurons. Evidence has been provided for a mechanism whereby astrocytes respond to glutamatergic activity by enhancing their glycolytic activity, resulting in increased lactate release. This is accomplished via the uptake of glutamate by glial glutamate transporters, leading to activation of the Na+/K+ ATPase and a stimulation of astrocytic glycolysis. Several recent observations obtained both in vitro and in vivo with different approaches have reinforced this view of brain energetics. Such an understanding might be critically important, not only because it forms the basis of some classical functional brain imaging techniques but also because several neurodegenerative diseases exhibit diverse alterations in energy metabolism.

Index Entries

Energy metabolism glucose lactate functional brain imaging neurodegenerative diseases neurometabolic coupling 

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References

  1. 1.
    Attwell D. and Laughlin S. B. (2001). An energy budget for signaling in the grey matter of the brain. J. Cereb. Blood Flow Metab. 21, 1133–1145.PubMedCrossRefGoogle Scholar
  2. 2.
    Rothman D. L., Behar K. L., Hyder F., and Shulman R. G. (2003). In vivo NMR studies of the glutamate neurotransmitter flux and neuroenergetics: implications for brain function. Annu. Rev. Physiol. 65, 401–427.PubMedCrossRefGoogle Scholar
  3. 3.
    Wong-Riley M. T. T. (1989). Cytochrome oxidase: an endogenous metabolic marker for neuronal activity. Trends Neurosci. 12, 94–101.PubMedCrossRefGoogle Scholar
  4. 4.
    Nehlig A. and Pereira de Vasconcelos A. (1993). Glucose and ketone body utilization by the brain of neonatal rats. Prog. Neurobiol. 40, 163–221.PubMedCrossRefGoogle Scholar
  5. 5.
    Fox P. T., Raichle M. E., Mintun M. A., and Dence C. (1988). Nonoxidative glucose consumption during focal physiologic neural activity. Science 241, 462–464.PubMedCrossRefGoogle Scholar
  6. 6.
    Morgello S., Uson R. R., Schwartz E. J., and Haber, R. S. (1995). The human blood-brain barrier glucose transporter (GLUT1) is a glucose transporter of gray matter astrocytes. Glia 14, 43–54.PubMedCrossRefGoogle Scholar
  7. 7.
    Yu S. and Ding, W. G. (1998). The 45 kDa form of glucose transporter 1 (GLUT1) is localized in oligodendrocyte and astrocyte but not in microglia in the rat brain. Brain Res. 797, 65–72.PubMedCrossRefGoogle Scholar
  8. 8.
    Golgi C. (1886). Sulla Fina Anatomia degli Organi Centrali del Sistema Nervosa. Hoepli, Milano, pp. 214; footnote on p. 154.Google Scholar
  9. 9.
    Porter J. T. and McCarthy K. D. (1997). Astrocytic neurotransmitter receptors in situ and in vivo. Prog. Neurobiol. 51, 439–455.PubMedCrossRefGoogle Scholar
  10. 10.
    Gadea A. and Lopez-Colome A. M. (2001). Glial transporters for glutamate, glycine and GABA I. Glutamate transporters. J. Neurosci. Res. 63, 453–460.PubMedCrossRefGoogle Scholar
  11. 11.
    Gadea A. and Lopez-Colome A. M. (2001). Glial transporters for glutamate, glycine, and GABA II. GABA transporters. J. Neurosci. Res. 63, 461–468.PubMedCrossRefGoogle Scholar
  12. 12.
    Gadea A. and Lopez-Colome A. M. (2001). Glial transporters for glutamate, glycine, and GABA III. Glycine transporters. J. Neurosci. Res. 64, 218–222.PubMedCrossRefGoogle Scholar
  13. 13.
    Schipke C. G. and Kettenmann H. (2004). Astrocyte responses to neuronal activity. Glia 47, 226–232.PubMedCrossRefGoogle Scholar
  14. 14.
    Haydon P. G. (2001). GLIA: listening and talking to the synapse. Nat. Rev. Neurosci. 2, 185–193.PubMedCrossRefGoogle Scholar
  15. 15.
    Pellerin L. and Magistretti P. J. (2004). Neuroenergetics: calling upon astrocytes to satisfy hungry neurons. Neuroscientist 10, 53–62.PubMedCrossRefGoogle Scholar
  16. 16.
    Pellerin L. and Magistretti P. J. (1994). Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc. Natl. Acad. Sci. USA. 91, 10,625–10,629.CrossRefGoogle Scholar
  17. 17.
    Chatton J. Y., Marquet P., and Magistretti P. J. (2000). A quantitative analysis of L-glutamate-regulated Na+ dynamics in mouse cortical astrocytes: implications for cellular bioenergetics. Eur. J. Neurosci. 12, 3843–3853.PubMedCrossRefGoogle Scholar
  18. 18.
    Pellerin L. and Magistretti P. J. (1997). Glutamate uptake stimulates Na+,K+-ATPase activity in astrocytes via activation of a distinct subunit highly sensitive to ouabain. J. Neurochem. 69, 2132–2137.PubMedCrossRefGoogle Scholar
  19. 19.
    Cholet N., Pellerin L., Magistretti P. J., and Hamel E. (2002). Similar perisynaptic glial localization for the Na+,K+-ATPase alpha 2 subunit and the glutamate transporters GLAST and GLT-1 in the rat somatosensory cortex. Cereb. Cortex. 12, 515–525.PubMedCrossRefGoogle Scholar
  20. 20.
    Chatton J. Y., Pellerin L., and Magistretti P. J. (2003). GABA uptake into astrocytes is not associated with significant metabolic cost: implications for brain imaging of inhibitory transmission. Proc. Natl. Acad. Sci. USA 100, 12,456–12,461.CrossRefGoogle Scholar
  21. 21.
    Loaiza A., Porras O. H., and Barros L. F. (2003). Glutamate triggers rapid glucose transport stimulation in astrocytes as evidenced by real-time confocal microscopy. J. Neurosci. 23, 7337–7342.PubMedGoogle Scholar
  22. 22.
    Akaoka H., Szymocha R., Beurton-Marduel P., Bernard A., Belin M. F., and Giraudon P. (2001). Functional changes in astrocytes by human T-lymphotropic virus type-1 T-lymphocytes. Virus Res. 78, 57–66.PubMedCrossRefGoogle Scholar
  23. 23.
    Ramos M., del Arco A., Pardo B., et al. (2003). Developmental changes in the Ca2+-regulated mitochondrial aspartate-glutamate carrier aralar1 in brain and prominent expression in the spinal cord. Dev. Brain Res. 143, 33–46.CrossRefGoogle Scholar
  24. 24.
    Hertz L., Swanson R. A., Newman G. C., Marrif H., Juurlink B. H., and Peng L. (1998). Can experimental conditions explain the discrepancy over glutamate stimulation of aerobic glycolysis? Dev. Neurosci. 20, 339–447.PubMedCrossRefGoogle Scholar
  25. 25.
    Peng L., Swanson R. A., Hertz L. (2001). Effects of L-glutamate, d-aspartate, and monensin on glycolytic and oxidative glucose metabolism in mouse astrocyte cultures: further evidence that glutamate uptake is metabolically driven by oxidative metabolism. Neurochem. Int. 38, 437–443.PubMedCrossRefGoogle Scholar
  26. 26.
    Brunet J. F., Grollimund L., Chatton J.Y., et al. (2004). Early acquisition of typical metabolic features upon differentiation of mouse neural stem cells into astrocytes. Glia 46, 8–17.PubMedCrossRefGoogle Scholar
  27. 27.
    Kasischke K. A., Vishwasrao H. D., Fischer P. J., Zipfel W. R., and Webb W. W. (2004). Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis. Science 305, 99–103.PubMedCrossRefGoogle Scholar
  28. 28.
    Cholet N., Pellerin L., Welker E., et al. (2001). Local injection of antisense oligonucleotides targeted to the glial glutamate transporter GLAST decreases the metabolic response to somatosensory activation J. Cereb. Blood Flow Metab. 21, 404–412.PubMedCrossRefGoogle Scholar
  29. 29.
    Voutsinos-Porche B., Bonvento G., Tanaka K., et al. (2003). Glial glutamate transporters mediate a functional metabolic crosstalk between neurons and astrocytes in the mouse developing cortex. Neuron 37, 275–286.PubMedCrossRefGoogle Scholar
  30. 30.
    Voutsinos-Porche B., Knott G., Tanaka K., Quairiaux C., Welker E., and Bonvento G. (2003). Glial glutamate transporters and maturation of the mouse somatosensory cortex. Cereb. Cortex. 13, 1110–1121.PubMedCrossRefGoogle Scholar
  31. 31.
    Nehlig A., Wittendorp-Rechenmann E., and Dao Lam C. (2004). Selective uptake of [14C]2-deoxyglucose by neurons and astrocytes: high-resolution microautoradiographic imaging by cellular 14C-trajectography combined with immunohistochemistry. J. Cereb. Blood Flow Metab. 24, 1004–1014.PubMedCrossRefGoogle Scholar
  32. 32.
    Porras O. H., Loaiza A., and Barros L. F. (2004). Glutamate mediates acute glucose transport inhibition in hippocampal neurons. J. Neurosci. 24, 9669–9673.PubMedCrossRefGoogle Scholar
  33. 33.
    Pellerin L. and Magistretti P. J. (2003). How to balance the brain energy budget while spending glucose differently. J. Physiol. 546, 325.PubMedCrossRefGoogle Scholar
  34. 34.
    Vǵa C., Martiel J. L., Drouhault D., Burckhart M. F., and Coles J. A. (2003). Uptake of locally applied deoxyglucose, glucose and lactate by axons and Schwann cells of rat vagus nerve. J. Physiol. 546, 551–564.CrossRefGoogle Scholar
  35. 35.
    Vǵa C., Poitry-Yamate C. L., Jirounek P., Tsacopoulos M., and Coles J. A. (1998). Lactate is released and taken up by isolated rabbit vagus nerve during aerobic metabolism. J. Neurochem. 71, 330–337.Google Scholar
  36. 36.
    Schurr A., Miller J. J., Payne R. S., and Rigor B. M. (1999). An increase in lactate output by brain tissue serves to meet the energy needs of glutamate-activated neurons. J. Neurosci. 19, 34–39.PubMedGoogle Scholar
  37. 37.
    Serres S., Bouyer J. J., Bezancon E., Canioni P., and Merle M. (2003). Involvement of brain lactate in neuronal metabolism. NMR Biomed. 16, 430–439.PubMedCrossRefGoogle Scholar
  38. 38.
    Serres S., Bezancon E., Franconi J. M., and Merle M. (2004). Ex vivo analysis of lactate and glucose metabolism in the rat brain under different states of depressed activity. J. Biol. Chem. 279, 47,881–47,889.CrossRefGoogle Scholar
  39. 39.
    Pellerin L. (2003). Lactate as a pivotal element in neuron-glia metabolic cooperation. Neurochem. Int. 43, 331–338.PubMedCrossRefGoogle Scholar
  40. 40.
    McIlwain H. (1953). Substances which support respiration and metabolic response to electrical impulses in human cerebral tissues. J. Neurol. Neurosurg. Psychiatry 16, 257–266.PubMedCrossRefGoogle Scholar
  41. 41.
    Ide T., Steinke J., and Cahill G. F., Jr. (1969). Metabolic interactions of glucose, lactate, and β-hydroxybutyrate in rat brain slices. Am. J. Physiol. 217, 784–792.PubMedGoogle Scholar
  42. 42.
    Fernandez E. and Medina J. M. (1986). Lactate utilization by the neonatal rat brain in vitro. Competition with glucose and 3-hydroxybutyrate. Biochem. J. 234, 489–492.PubMedGoogle Scholar
  43. 43.
    Vicario C., Arizmendi C., Malloch G., Clark J. B., and Medina J. M. (1991). Lactate utilization by isolated cells from early neonatal rat brain. J. Neurochem. 57, 1700–1707.PubMedCrossRefGoogle Scholar
  44. 44.
    Tabernero A., Vicario C., and Medina J. M. (1996). Lactate spares glucose as a metabolic fuel in neurons and astrocytes from primary culture. Neurosci. Res. 26, 369–376.PubMedCrossRefGoogle Scholar
  45. 45.
    McKenna M. C., Hopkins I. B., and Carey A. (2001). α-cyano-4-hydroxycinnamate decreases both glucose and lactate metabolism in neurons and astrocytes: implications for lactate as an energy substrate for neurons. J. Neurosci. Res. 66, 747–754.PubMedCrossRefGoogle Scholar
  46. 46.
    Honegger P., Braissant O., Henry H., et al. (2002). Alteration of amino acid metabolism in neuronal aggregate cultures exposed to hypoglycaemic conditions. J. Neurochem. 81, 1141–1151.PubMedCrossRefGoogle Scholar
  47. 47.
    Larrabee M. G. (1983). Lactate uptake and release in the presence of glucose by sympathetic ganglia of chicken embryos and by neuronal and nonneuronal cultures prepared from these ganglia. J. Neurochem. 40, 1237–1250.PubMedGoogle Scholar
  48. 48.
    Larrabee M. G. (1992). Extracellular intermediates of glucose metabolism: fluxes of endogenous lactate and alanine through extracellular pools in embryonic sympathetic ganglia. J. Neurochem. 59, 1041–1052.PubMedCrossRefGoogle Scholar
  49. 49.
    Larrabee M. G. (1995). Lactate metabolism and its effect on glucose metabolism in an excised neural tissue. J. Neurochem. 64, 1734–1741.PubMedCrossRefGoogle Scholar
  50. 50.
    Larrabee M. G. (1996). Partitioning of CO2 production between glucose and lactate in excised sympathetic ganglia, with implications for brain. J. Neurochem. 67, 1726–1734.PubMedCrossRefGoogle Scholar
  51. 51.
    McKenna M. C., Tildon J. T., Stevenson J. H., Boatright R., and Huang S. (1993). Regulation of energy metabolism in synaptic terminals and cultured rat brain astrocytes: differences revealed using aminooxyacetate. Dev. Neurosci. 15, 320–329.PubMedGoogle Scholar
  52. 52.
    McKenna M. C., Tildon J. T., Stevenson J. H., and Hopkins I. B. (1994). Energy metabolism in cortical synaptic terminals from weanling and mature rat brain: evidence for multiple compartments of tricarboxylic acid cycle activity. Dev. Neurosci. 16, 291–300.PubMedGoogle Scholar
  53. 53.
    McKenna M. C., Tildon J. T., Stevenson J. H., Hopkins I. B., Huang X., and Couto R. (1998). Lactate transport by cortical synaptosomes from adult brain: characterization of kinetics and inhibitor specificity. Dev. Neurosci. 20, 300–309.PubMedCrossRefGoogle Scholar
  54. 54.
    Itoh Y., Esaki T., Shimoji K., et al. (2003). Dichloroacetate effects on glucose and lactate oxidation by neurons and astroglia in vitro and on glucose utilization by brain in vivo. Proc. Natl. Acad. Sci. USA 100, 4879–4884.PubMedCrossRefGoogle Scholar
  55. 55.
    Bouzier-Sore A. K., Voisin P., Canioni P., Magistretti P. J., and Pellerin L. (2003) Lactate is a preferential oxidative energy substrate over glucose for neurons in culture. J. Cereb. Blood Flow Metab. 23, 1298–1306.PubMedCrossRefGoogle Scholar
  56. 56.
    Bouzier A. K., Thiaudiere E., Biran M., Rouland R., Canioni P., and Merle M. (2000). The metabolism of [3-(13)C]lactate in the rat brain is specific of a pyruvate carboxylase-deprived compartment. J. Neurochem. 75, 480–486.PubMedCrossRefGoogle Scholar
  57. 57.
    Hassel B. and Brathe A. (2000). Cerebral metabolism of lactate in vivo: evidence for neuronal pyruvate carboxylation. J. Cereb. Blood Flow Metab. 20, 327–336.PubMedCrossRefGoogle Scholar
  58. 58.
    Qu H., Haberg A., Haraldseth O., Unsgard G., and Sonnewald U. (2000). (13)C MR spectroscopy study of lactate as substrate for rat brain. Dev. Neurosci. 22, 429–436.PubMedCrossRefGoogle Scholar
  59. 59.
    Smith D., Pernet A., Hallett W. A., Bingham E., Marsden P. K., and Amiel S. A. (2003). Lactate: a preferred fuel for human brain metabolism in vivo. J. Cereb. Blood Flow Metab. 23, 658–664.PubMedCrossRefGoogle Scholar
  60. 60.
    Mangia S., Garreffa G., Bianciardi M., Giove F., Di Salle F., and Maraviglia B. (2003). The aerobic brain: lactate decrease at the onset of neural activity. Neuroscience 118, 7–10.PubMedCrossRefGoogle Scholar
  61. 61.
    Hu Y. and Wilson G. S. (1997). A temporary local energy pool coupled to neuronal activity: fluctuations of extracellular lactate levels in rat brain monitored with rapid-response enzyme-based sensor. J. Neurochem. 69, 1484–1490.PubMedCrossRefGoogle Scholar
  62. 62.
    Prichard J., Rothman D., Novotny E., et al. (1991). Lactate rise detected by 1H NMR in human visual cortex during physiologic stimulation. Proc. Natl. Acad. Sci. USA 88, 5829–5831.PubMedCrossRefGoogle Scholar
  63. 63.
    Fellows L. K., Boutelle M. G., and Fillenz M. (1993). Physiological stimulation increases nonoxidative glucose metabolism in the brain of the freely moving rat. J. Neurochem. 60, 1258–1263.PubMedCrossRefGoogle Scholar
  64. 64.
    Frahm J., Kruger G., Merboldt K. D., and Kleinschmidt A. (1996). Dynamic uncoupling and recoupling of perfusion and oxidative metabolism during focal brain activation in man. Magn. Reson. Med. 35, 143–148.PubMedCrossRefGoogle Scholar
  65. 65.
    Abi-Saab W. M., Maggs D. G., Jones T., et al. (2002). Striking differences in glucose and lactate levels between brain extracellular fluid and plasma in conscious human subjects: effects of hyperglycemia and hypoglycemia. J. Cereb. Blood Flow Metab. 22, 271–279.PubMedCrossRefGoogle Scholar
  66. 66.
    Pellerin L. and Magistretti P. J. (2003). Food for thought: challenging the dogmas. J. Cereb. Blood Flow Metab. 23, 1282–1286.PubMedCrossRefGoogle Scholar
  67. 67.
    Bittar P. G., Charnay Y., Pellerin L., Bouras C., and Magistretti P. J. (1996). Selective distribution of lactate dehydrogenase isoenzymes in neurons and astrocytes of human brain. J. Cereb. Blood Flow Metab. 16, 1079–1089.PubMedCrossRefGoogle Scholar
  68. 68.
    Laughton J. D., Charnay Y., Belloir B., Pellerin L., Magistretti P. J., and Bouras C. (2000). Differential messenger RNA distribution of lactate dehydrogenase LDH-1 and LDH-5 isoforms in the rat brain. Neuroscience 96, 619–625.PubMedCrossRefGoogle Scholar
  69. 69.
    Pierre K. and Pellerin L. (2005). Monocarboxylite transporters in the central nervous system: distribution, regulation and function. J. Neurochem. 94, 1–14.PubMedCrossRefGoogle Scholar
  70. 70.
    Pellerin L., Begersen L., Halestrap A. P., and Pierre K. (2005). Cellular and subcellular distribution of monocarboxylate transporters in cultured brain cells and in the adult brain. J. Neurosci. Res. 79, 55–64.PubMedCrossRefGoogle Scholar
  71. 71.
    Brër S., Rahman B., Pellegri G., et al. (1997). Comparison of lactate transport in astroglial cells and monocarboxylate transporter 1 (MCT1) expressing Xenopus laevis oocytes: expression of two different monocarboxylate transporters in astroglial cells and neurons. J. Biol. Chem. 272, 30,096–30,102.Google Scholar
  72. 72.
    Hanu R., McKenna M., O’Neill A., Resneck W. G., and Bloch R. J. (2000). Monocarboxylic acid transporters, MCT1 and MCT2, in cortical astrocytes in vitro and in vivo. Am. J. Physiol. 278, C921-C930.Google Scholar
  73. 73.
    Pierre K., Pellerin L., Debernardi R., Riederer B. M., and Magistretti P. J. (2000). Cell-specific localization of monocarboxylate transporters, MCT1 and MCT2, in the adult mouse brain revealed by double immunohistochemical labeling and confocal microscopy. Neuroscience 100, 617–627.PubMedCrossRefGoogle Scholar
  74. 74.
    Bergersen L., Rafiki A., and Ottersen O. P. (2002). Immunogold cytochemistry identifies specialized membrane domains for monocarboxylate transport in the central nervous system. Neurochem. Res. 27, 89–96.PubMedCrossRefGoogle Scholar
  75. 75.
    Debernardi R., Pierre K., Lengacher S., Magistretti P. J., and Pellerin L. (2003). Cell-specific expression pattern of monocarboxylate transporters in astrocytes and neurons observed in different mouse brain cortical cell cultures. J. Neurosci. Res. 73, 141–155.PubMedCrossRefGoogle Scholar
  76. 76.
    Rafiki A., Boulland J. L., Halestrap A. P. Ottersen O. P., and Bergersen L. (2003). Highly differential expression of the monocarboxylate transporters MCT2 and MCT4 in the developing rat brain. Neuroscience 122, 677–688.PubMedCrossRefGoogle Scholar
  77. 77.
    Bergersen L., Waerhaug O., Helm J., et al.. (2001). A novel postsynaptic density protein: the monocarboxylate transporter MCT2 is colocalized with δ-glutamate receptors in postsynaptic densities of parallel fiber-Purkinje cell synapses. Exp. Brain Res. 136, 523–534.PubMedCrossRefGoogle Scholar
  78. 78.
    Pierre K., Magistretti P. J., and Pellerin L. (2002). MCT2 is a major neuronal monocarboxylate transporter in the adult mouse brain. J. Cereb. Blood Flow Metab. 22, 586–595.PubMedCrossRefGoogle Scholar
  79. 79.
    Bergersen L., Magistretti P. J., and Pellerin L. (2004). Selective postsynaptic co-localisation of MCT2 with AMPA receptor GluR2/3 subunits at excitatory synapses exhibiting AMPA receptor trafficking. Cerebral Cortex (Epub).Google Scholar
  80. 80.
    Bliss T. M., Ip M., Cheng E., et al. (2004). Dualgene, dual-cell type therapy against an excitotoxic insult by bolstering neuroenergetics. J. Neurosci. 24, 6202–6208.PubMedCrossRefGoogle Scholar
  81. 81.
    Pierre K., Debernardi R., Magistretti P. J., and Pellerin L. (2003). Noradrenaline enhances monocarboxylate transporter 2 expression in cultured mouse cortical neurons via a translational regulation. J. Neurochem. 86, 1468–1476.PubMedCrossRefGoogle Scholar
  82. 82.
    Mazziotta J. C., Phelps M. E., Pahl J. J., et al. (1987). Reduced cerebral glucose metabolism in asymptomatic subjects at risk for Huntington’s disease. N. Engl. J. Med. 316, 357–362.PubMedCrossRefGoogle Scholar
  83. 83.
    Reiman E. M., Caselli R. J., Yun L. S., et al. (1996). Preclinical evidence of Alzheimer’s disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. N. Engl. J. Med. 334, 752–758PubMedCrossRefGoogle Scholar
  84. 84.
    Back T., Zhao W., and Ginsberg M. D. (1995). Three-dimensional image analysis of brain glucose metabolism-blood flow uncoupling and its electrophysiological correlates in the acute ischemic penumbra following middle cerebral artery occlusion. J. Cereb. Blood Flow Metab. 15, 566–577.PubMedGoogle Scholar
  85. 85.
    Bruehl C., Hagemann G., and Witte O. W. (1998). Uncoupling of blood flow and metabolism in focal epilepsy. Epilepsia. 39, 1235–1242.PubMedCrossRefGoogle Scholar
  86. 86.
    Molnar M. J., Valikovics A., Molnar S., et al. (2000). Cerebral blood flow and glucose metabolism in mitochondrial disorders. Neurology 55, 544–588.PubMedGoogle Scholar
  87. 87.
    Tagamets M. A. and Horwitz B. (2001). Interpreting PET and fMRI measures of functional neural activity: the effects of synaptic inhibition on cortical activation in human imaging studies. Brain Res. Bull. 54, 267–273.PubMedCrossRefGoogle Scholar
  88. 88.
    Arthurs O. J. and Boniface S. (2002). How well do we understand the neural origins of the fMRI BOLD signal? Trends Neurosci. 25, 27–31.PubMedCrossRefGoogle Scholar
  89. 89.
    Waldvogel D., van Gelderen P., Muellbacher W., Ziemann U., Immisch I., and Hallett M. (2000). The relative metabolic demand of inhibition and excitation. Nature 406, 995–998.PubMedCrossRefGoogle Scholar
  90. 90.
    Bernardinelli Y., Magistretti P. J., and Chatton J. Y. (2004). Astrocytes generate Na+-mediated metabolic waves. Proc. Natl. Acad. Sci. USA 101, 14,937–14,942.CrossRefGoogle Scholar
  91. 91.
    Izumi Y., Benz A. M., Katsuki H., and Zorumski C. F. (1997). Endogenous monocarboxylates sustain hippocampal synaptic function and morphological integrity during energy deprivation. J. Neurosci. 17, 9448–9457.PubMedGoogle Scholar
  92. 92.
    Schurr A., Payne R. S., Miller J. J., and Rigor B. M. (1997). Brain lactate, not glucose, fuels the recovery of synaptic function from hypoxia upon reoxygenation: an in vitro study. Brain Res. 744, 105–111.PubMedCrossRefGoogle Scholar
  93. 93.
    Schurr A., Payne R. S., Miller J. J., and Rigor B. M. (1997). Glia are the main source of lactate utilized by neurons for recovery of function posthypoxia. Brain Res. 774, 221–224.PubMedCrossRefGoogle Scholar
  94. 94.
    Cater H. L., Benham C. D., and Sundstrom L. E. (2001). Neuroprotective role of monocarboxylate transport during glucose deprivation in slices culture of rat hippocampus. J. Physiol. (Lond) 531, 459–466.CrossRefGoogle Scholar
  95. 95.
    Cater H. L., Chandratheva A., Benham C. D., Morrison B., and Sundstrom L. E. (2003). Lactate and glucose as energy substrates during, and after, oxygen deprivation in rat hippocampal acute and cultured slices. J. Neurochem. 87, 1381–1390.PubMedCrossRefGoogle Scholar
  96. 96.
    Schurr A., Payne R. S., Miller J. J., Tseng M. T., Rigor B. M. (2001). Blockade of lactate transport exacerbates delayed neuronal damage in a rat model of cerebral ischemia. Brain Res. 895, 268–272.PubMedCrossRefGoogle Scholar
  97. 97.
    Mendelowitsch A., Ritz M. F., Ros J., Langemann H., and Gratzl O. (2001). 17β-Estradiol reduces cortical lesion size in the glutamate excitotoxicity model by enhancing extracellular lactate: a new neuroprotective pathway. Brain Res. 901, 230–236.PubMedCrossRefGoogle Scholar
  98. 98.
    Ros J., Pecinska N., Alessandri B., Landolt H., Fillenz M. (2001). Lactate reduces glutamate-induced neurotoxicity in rat cortex. J. Neurosci. Res. 66, 790–794.PubMedCrossRefGoogle Scholar
  99. 99.
    Sapolsky R. M. (2003). Neuroprotective gene therapy against acute neurological insults. Nat. Rev. Neurosci. 4, 61–69.PubMedCrossRefGoogle Scholar
  100. 100.
    Lynch G. (2004). AMPA receptor modulators as cognitive enhancers. Curr. Opin. Pharmacol. 4, 4–11.PubMedCrossRefGoogle Scholar
  101. 101.
    Pellerin L. and Magistretti P. J. (2005). Ampakine CX546 bolsters energetic response of astrocytes: a novel target for cognitive-enhancing drugs acting as AMPA receptor modulators. J. Neurochem., 92, 668–677.PubMedCrossRefGoogle Scholar

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© Humana Press Inc 2005

Authors and Affiliations

  1. 1.Département de PhysiologieUniversité de LausanneSwitzerland

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