Skip to main content
SpringerLink
Log in

Glutamate and ATP at the Interface Between Signaling and Metabolism in Astroglia: Examples from Pathology

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Glutamate is the main excitatory transmitter in the brain, while ATP represents the most important energy currency in any living cell. Yet, these chemicals play an important role in both processes, enabling them with dual-acting functions in metabolic and intercellular signaling pathways. Glutamate can fuel ATP production, while ATP can act as a transmitter in intercellular signaling. We discuss the interface between glutamate and ATP in signaling and metabolism of astrocytes. Not only do glutamate and ATP cross each other’s paths in physiology of the brain, but they also do so in its pathology. We present the fabric of this process in (patho)physiology through the discussion of synthesis and metabolism of ATP and glutamate in astrocytes as well as by providing a general description of astroglial receptors for these molecules along with the downstream signaling pathways that may be activated. It is astroglial receptors for these dual-acting molecules that could hold a key for medical intervention in pathological conditions. We focus on two examples disclosing the role of activation of astroglial ATP and glutamate receptors in pathology of two kinds of brain tissue, gray matter and white matter, respectively. Interventions at the interface of metabolism and signaling show promise for translational medicine.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Miller SL (1953) A production of amino acids under possible primitive earth conditions. Science 117:528–529

    Article  CAS  PubMed  Google Scholar 

  2. Glavin DP, Callahan MP, Dworkin JP, Elsila JE (2011) The effects of parent body processes on amino acids in carbonaceous chondrites. Meteorit Planet Sci 45:1948–1972

    Article  CAS  Google Scholar 

  3. Schousboe A (1981) Transport and metabolism of glutamate and GABA in neurons are glial cells. Int Rev Neurobiol 22:1–45

    Article  CAS  PubMed  Google Scholar 

  4. Wadiche JI, Arriza JL, Amara SG, Kavanaugh MP (1995) Kinetics of a human glutamate transporter. Neuron 14:1019–1027

    Article  CAS  PubMed  Google Scholar 

  5. Robinson MB, Dowd LA (1997) Heterogeneity and functional properties of subtypes of sodium-dependent glutamate transporters in the mammalian central nervous system. Adv Pharmacol 37:69–115

    Article  CAS  PubMed  Google Scholar 

  6. Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105

    Article  CAS  PubMed  Google Scholar 

  7. Schousboe A, Walls AB, Bak LK, Waagepetersen HS (2015) Astroglia and brain metabolism: focus on energy and neurotransmitter amino acid homeostasis. In: Verkhratsky A, Parpura V (eds) Colloquium series on neuroglia in biology and medicine: from physiology to disease. Morgan & Claypool Publishers. doi:10.4199/C00130ED00131V00101Y201506NGL201007

  8. Schousboe A (2012) Studies of brain metabolism: a historical perspective. Adv Neurobiol 4:909–920

    Article  Google Scholar 

  9. Norenberg MD, Martinez-Hernandez A (1979) Fine structural localization of glutamine synthetase in astrocytes of rat brain. Brain Res 161:303–310

    Article  CAS  PubMed  Google Scholar 

  10. McKenna MC (2007) The glutamate-glutamine cycle is not stoichiometric: fates of glutamate in brain. J Neurosci Res 85:3347–3358

    Article  CAS  PubMed  Google Scholar 

  11. McKenna MC, Dienel GA, Sonnewald U, Waagepetersen HS, Schousboe A (2012) Energy metabolism of the brain. In: Siegel GJ, Agranoff BW, Albers RW, Fisher SK, Uhler MD (eds) Basic neurochemistry: molecular, cellular, and medical aspects. Elsevier-Academic Press, London, pp 200–231

    Chapter  Google Scholar 

  12. Westergaard N, Sonnewald U, Schousboe A (1995) Metabolic trafficking between neurons and astrocytes: the glutamate/glutamine cycle revisited. Dev Neurosci 17:203–211

    Article  CAS  PubMed  Google Scholar 

  13. Yu AC, Drejer J, Hertz L, Schousboe A (1983) Pyruvate carboxylase activity in primary cultures of astrocytes and neurons. J Neurochem 41:1484–1487

    Article  CAS  PubMed  Google Scholar 

  14. Shank RP, Bennett GS, Freytag SO, Campbell GL (1985) Pyruvate carboxylase: an astrocyte-specific enzyme implicated in the replenishment of amino acid neurotransmitter pools. Brain Res 329:364–367

    Article  CAS  PubMed  Google Scholar 

  15. Westergaard N, Drejer J, Schousboe A, Sonnewald U (1996) Evaluation of the importance of transamination versus deamination in astrocytic metabolism of [U-13C]glutamate. Glia 17:160–168

    Article  CAS  PubMed  Google Scholar 

  16. McKenna MC (2013) Glutamate pays its own way in astrocytes. Front Endocrinol 4:191. doi:10.3389/fendo.2013.00191

    Article  Google Scholar 

  17. Cholet N, Pellerin L, Magistretti PJ, 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

    Article  CAS  PubMed  Google Scholar 

  18. Rose EM, Koo JC, Antflick JE, Ahmed SM, Angers S, Hampson DR (2009) Glutamate transporter coupling to Na, K-ATPase. J Neurosci 29:8143–8155

    Article  CAS  PubMed  Google Scholar 

  19. Schousboe A, Sickmann HM, Bak LK, Schousboe I, Jajo FS, Faek SA, Waagepetersen HS (2011) Neuron-glia interactions in glutamatergic neurotransmission: roles of oxidative and glycolytic adenosine triphosphate as energy source. J Neurosci Res 89:1926–1934

    Article  CAS  PubMed  Google Scholar 

  20. Genda EN, Jackson JG, Sheldon AL, Locke SF, Greco TM, O’Donnell JC, Spruce LA, Xiao R, Guo W, Putt M, Seeholzer S, Ischiropoulos H, Robinson MB (2011) Co-compartmentalization of the astroglial glutamate transporter, GLT-1, with glycolytic enzymes and mitochondria. J Neurosci 31:18275–18288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bauer DE, Jackson JG, Genda EN, Montoya MM, Yudkoff M, Robinson MB (2012) The glutamate transporter, GLAST, participates in a macromolecular complex that supports glutamate metabolism. Neurochem Int 61:566–574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Pajecka K, Nissen JD, Stridh MH, Skytt DM, Schousboe A, Waagepetersen HS (2015) Glucose replaces glutamate as energy substrate to fuel glutamate uptake in glutamate dehydrogenase-deficient astrocytes. J Neurosci Res 93:1093–1100

    Article  CAS  PubMed  Google Scholar 

  23. Jackson JG, O’Donnell JC, Takano H, Coulter DA, Robinson MB (2014) Neuronal activity and glutamate uptake decrease mitochondrial mobility in astrocytes and position mitochondria near glutamate transporters. J Neurosci 34:1613–1624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Schousboe A (2016) A tribute to Mary C. McKenna: Glutamate as energy substrate and neurotransmitter: functional interaction between neurons and astrocytes. Neurochem Res. doi:10.1007/s11064-015-1813-9

    PubMed Central  Google Scholar 

  25. Yu AC, Schousboe A, Hertz L (1982) Metabolic fate of 14C-labeled glutamate in astrocytes in primary cultures. J Neurochem 39:954–960

    Article  CAS  PubMed  Google Scholar 

  26. Nissen JD, Pajecka K, Stridh MH, Skytt DM, Waagepetersen HS (2015) Dysfunctional TCA-cycle metabolism in glutamate dehydrogenase deficient astrocytes. Glia 63:2313–2326

    Article  PubMed  Google Scholar 

  27. Karaca M, Frigerio F, Migrenne S, Martin-Levilain J, Skytt DM, Pajecka K, Martin-Del-Rio R, Gruetter R, Tamarit-Rodriguez J, Waagepetersen HS, Magnan C, Maechler P (2015) GDH-dependent glutamate oxidation in the brain dictates peripheral energy substrate distribution. Cell Rep 13:365–375

    Article  CAS  PubMed  Google Scholar 

  28. McKenna MC, Tildon JT, Stevenson JH, Boatright R, Huang S (1993) Regulation of energy metabolism in synaptic terminals and cultured rat brain astrocytes: differences revealed using aminooxyacetate. Dev Neurosci 15:320–329

    Article  CAS  PubMed  Google Scholar 

  29. Sonnewald U (2014) Glutamate synthesis has to be matched by its degradation - where do all the carbons go? J Neurochem 131:399–406

    Article  CAS  PubMed  Google Scholar 

  30. Skytt DM, Klawonn AM, Stridh MH, Pajecka K, Patruss Y, Quintana-Cabrera R, Bolanos JP, Schousboe A, Waagepetersen HS (2012) siRNA knock down of glutamate dehydrogenase in astrocytes affects glutamate metabolism leading to extensive accumulation of the neuroactive amino acids glutamate and aspartate. Neurochem Int 61:490–497

    Article  CAS  PubMed  Google Scholar 

  31. Raju K, Doulias PT, Evans P, Krizman EN, Jackson JG, Horyn O, Daikhin Y, Nissim I, Yudkoff M, Nissim I, Sharp KA, Robinson MB, Ischiropoulos H (2015) Regulation of brain glutamate metabolism by nitric oxide and S-nitrosylation. Sci Signal 8:ra68

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Parpura V, Zorec R (2010) Gliotransmission: exocytotic release from astrocytes. Brain Res Rev 63:83–92

    Article  CAS  PubMed  Google Scholar 

  33. Malarkey EB, Parpura V (2009) Mechanisms of transmitter release from astrocytes. In: Parpura V, Haydon PG (eds) Astrocytes in (patho)physiology of the nervous system. Springer, New York, pp 301–350

    Chapter  Google Scholar 

  34. Verkhratsky A, Matteoli M, Parpura V, Mothet JP, Zorec R (2016) Astrocytes as secretory cells of the central nervous system: idiosyncrasies of vesicular secretion. EMBO J. 35:239–257. doi:10.15252/embj.201592705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bowman CL, Kimelberg HK (1984) Excitatory amino acids directly depolarize rat brain astrocytes in primary culture. Nature 311:656–659

    Article  CAS  PubMed  Google Scholar 

  36. Kettenmann H, Backus KH, Schachner M (1984) Aspartate, glutamate and gamma-aminobutyric acid depolarize cultured astrocytes. Neurosci Lett 52:25–29

    Article  CAS  PubMed  Google Scholar 

  37. Kettenmann H, Gilbert P, Schachner M (1984) Depolarization of cultured oligodendrocytes by glutamate and GABA. Neurosci Lett 47:271–276

    Article  CAS  PubMed  Google Scholar 

  38. Condorelli DF, Conti F, Gallo V, Kirchhoff F, Seifert G, Steinhauser C, Verkhratsky A, Yuan X (1999) Expression and functional analysis of glutamate receptors in glial cells. Adv Exp Med Biol 468:49–67

    Article  CAS  PubMed  Google Scholar 

  39. Seifert G, Steinhauser C (2001) Ionotropic glutamate receptors in astrocytes. Prog Brain Res 132:287–299

    Article  CAS  PubMed  Google Scholar 

  40. Steinhäuser C, Gallo V (1996) News on glutamate receptors in glial cells. Trends Neurosci 19:339–345

    Article  PubMed  Google Scholar 

  41. Verkhratsky A, Kirchhoff F (2007) Glutamate-mediated neuronal-glial transmission. J Anat 210:651–660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hollmann M, Heinemann S (1994) Cloned glutamate receptors. Annu Rev Neurosci 17:31–108

    Article  CAS  PubMed  Google Scholar 

  43. Wisden W, Seeburg PH (1993) Mammalian ionotropic glutamate receptors. Curr Opin Neurobiol 3:291–298

    Article  CAS  PubMed  Google Scholar 

  44. Gallo V, Ghiani CA (2000) Glutamate receptors in glia: new cells, new inputs and new functions. Trends Pharmacol Sci 21:252–258

    Article  CAS  PubMed  Google Scholar 

  45. Verkhratsky A, Steinhauser C (2000) Ion channels in glial cells. Brain Res Brain Res Rev 32:380–412

    Article  CAS  PubMed  Google Scholar 

  46. Seeburg PH, Higuchi M, Sprengel R (1998) RNA editing of brain glutamate receptor channels: mechanism and physiology. Brain Res Brain Res Rev 26:217–229

    Article  CAS  PubMed  Google Scholar 

  47. Burnashev N (1998) Calcium permeability of ligand-gated channels. Cell Calcium 24:325–332

    Article  CAS  PubMed  Google Scholar 

  48. Lerma J (2003) Roles and rules of kainate receptors in synaptic transmission. Nat Rev Neurosci 4:481–495

    Article  CAS  PubMed  Google Scholar 

  49. Reiner A, Arant RJ, Isacoff EY (2012) Assembly stoichiometry of the GluK2/GluK5 kainate receptor complex. Cell Rep 1:234–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Garcia-Barcina JM, Matute C (1996) Expression of kainate-selective glutamate receptor subunits in glial cells of the adult bovine white matter. Eur J Neurosci 8:2379–2387

    Article  CAS  PubMed  Google Scholar 

  51. Brand-Schieber E, Lowery SL, Werner P (2004) Select ionotropic glutamate AMPA/kainate receptors are expressed at the astrocyte-vessel interface. Brain Res 1007:178–182

    Article  CAS  PubMed  Google Scholar 

  52. Stephenson FA (2006) Structure and trafficking of NMDA and GABAA receptors. Biochem Soc Trans 34:877–881

    Article  CAS  PubMed  Google Scholar 

  53. Teng H, Cai W, Zhou L, Zhang J, Liu Q, Wang Y, Dai W, Zhao M, Sun Z (2010) Evolutionary mode and functional divergence of vertebrate NMDA receptor subunit 2 genes. PLoS One 5:e13342

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Pachernegg S, Strutz-Seebohm N, Hollmann M (2012) GluN3 subunit-containing NMDA receptors: not just one-trick ponies. Trends Neurosci 35:240–249

    Article  CAS  PubMed  Google Scholar 

  55. Lalo U, Pankratov Y, Kirchhoff F, North RA, Verkhratsky A (2006) NMDA receptors mediate neuron-to-glia signaling in mouse cortical astrocytes. J Neurosci 26:2673–2683

    Article  CAS  PubMed  Google Scholar 

  56. Ziak D, Chvatal A, Sykova E (1998) Glutamate-, kainate- and NMDA-evoked membrane currents in identified glial cells in rat spinal cord slice. Physiol Res 47:365–375

    CAS  PubMed  Google Scholar 

  57. Schipke CG, Ohlemeyer C, Matyash M, Nolte C, Kettenmann H, Kirchhoff F (2001) Astrocytes of the mouse neocortex express functional N-methyl-d-aspartate receptors. Faseb J 15:1270–1272

    CAS  PubMed  Google Scholar 

  58. Conti F, DeBiasi S, Minelli A, Melone M (1996) Expression of NR1 and NR2A/B subunits of the NMDA receptor in cortical astrocytes. Glia 17:254–258

    Article  CAS  PubMed  Google Scholar 

  59. Mayer ML, Westbrook GL, Guthrie PB (1984) Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature 309:261–263

    Article  CAS  PubMed  Google Scholar 

  60. Nowak L, Bregestovski P, Ascher P, Herbet A, Prochiantz A (1984) Magnesium gates glutamate-activated channels in mouse central neurones. Nature 307:462–465

    Article  CAS  PubMed  Google Scholar 

  61. Ascher P, Nowak L (1988) The role of divalent cations in the N-methyl-d-aspartate responses of mouse central neurones in culture. J Physiol 399:247–266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Palygin O, Lalo U, Pankratov Y (2011) Distinct pharmacological and functional properties of NMDA receptors in mouse cortical astrocytes. Br J Pharmacol 163:1755–1766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Palygin O, Lalo U, Verkhratsky A, Pankratov Y (2010) Ionotropic NMDA and P2X1/5 receptors mediate synaptically induced Ca2+ signalling in cortical astrocytes. Cell Calcium 48:225–231

    Article  CAS  PubMed  Google Scholar 

  64. Karadottir R, Cavelier P, Bergersen LH, Attwell D (2005) NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. Nature 438:1162–1166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Micu I, Jiang Q, Coderre E, Ridsdale A, Zhang L, Woulfe J, Yin X, Trapp BD, McRory JE, Rehak R, Zamponi GW, Wang W, Stys PK (2006) NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia. Nature 439:988–992

    CAS  PubMed  Google Scholar 

  66. Salter MG, Fern R (2005) NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury. Nature 438:1167–1171

    Article  CAS  PubMed  Google Scholar 

  67. Burzomato V, Frugier G, Perez-Otano I, Kittler JT, Attwell D (2010) The receptor subunits generating NMDA receptor mediated currents in oligodendrocytes. J Physiol 588:3403–3414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ferraguti F, Shigemoto R (2006) Metabotropic glutamate receptors. Cell Tissue Res 326:483–504

    Article  CAS  PubMed  Google Scholar 

  69. Nakanishi S (1994) Metabotropic glutamate receptors: synaptic transmission, modulation, and plasticity. Neuron 13:1031–1037

    Article  CAS  PubMed  Google Scholar 

  70. Aronica E, van Vliet EA, Mayboroda OA, Troost D, da Silva FH, Gorter JA (2000) Upregulation of metabotropic glutamate receptor subtype mGluR3 and mGluR5 in reactive astrocytes in a rat model of mesial temporal lobe epilepsy. Eur J Neurosci 12:2333–2344

    Article  CAS  PubMed  Google Scholar 

  71. Petralia RS, Wang YX, Niedzielski AS, Wenthold RJ (1996) The metabotropic glutamate receptors, mGluR2 and mGluR3, show unique postsynaptic, presynaptic and glial localizations. Neuroscience 71:949–976

    Article  CAS  PubMed  Google Scholar 

  72. Tamaru Y, Nomura S, Mizuno N, Shigemoto R (2001) Distribution of metabotropic glutamate receptor mGluR3 in the mouse CNS: differential location relative to pre- and postsynaptic sites. Neuroscience 106:481–503

    Article  CAS  PubMed  Google Scholar 

  73. Catania MV, De Socarraz H, Penney JB, Young AB (1994) Metabotropic glutamate receptor heterogeneity in rat brain. Mol Pharmacol 45:626–636

    CAS  PubMed  Google Scholar 

  74. Cai Z, Schools GP, Kimelberg HK (2000) Metabotropic glutamate receptors in acutely isolated hippocampal astrocytes: developmental changes of mGluR5 mRNA and functional expression. Glia 29:70–80

    Article  CAS  PubMed  Google Scholar 

  75. Sun W, McConnell E, Pare JF, Xu Q, Chen M, Peng W, Lovatt D, Han X, Smith Y, Nedergaard M (2013) Glutamate-dependent neuroglial calcium signaling differs between young and adult brain. Science 339:197–200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Wroblewska B, Santi MR, Neale JH (1998) N-acetylaspartylglutamate activates cyclic AMP-coupled metabotropic glutamate receptors in cerebellar astrocytes. Glia 24:172–179

    Article  CAS  PubMed  Google Scholar 

  77. Wroblewska B, Wegorzewska IN, Bzdega T, Olszewski RT, Neale JH (2006) Differential negative coupling of type 3 metabotropic glutamate receptor to cyclic GMP levels in neurons and astrocytes. J Neurochem 96:1071–1077

    Article  CAS  PubMed  Google Scholar 

  78. Kirischuk S, Kirchhoff F, Matyash V, Kettenmann H, Verkhratsky A (1999) Glutamate-triggered calcium signalling in mouse Bergmann glial cells in situ: role of inositol-1,4,5-trisphosphate-mediated intracellular calcium release. Neuroscience 92:1051–1059

    Article  CAS  PubMed  Google Scholar 

  79. Bodin P, Burnstock G (2001) Purinergic signalling: ATP release. Neurochem Res 26:959–969

    Article  CAS  PubMed  Google Scholar 

  80. North RA, Verkhratsky A (2006) Purinergic transmission in the central nervous system. Pflugers Arch 452:479–485

    Article  CAS  PubMed  Google Scholar 

  81. Lalo U, Pankratov Y, Parpura V, Verkhratsky A (2011) Ionotropic receptors in neuronal-astroglial signalling: what is the role of “excitable” molecules in non-excitable cells. Biochim Biophys Acta 1813:992–1002

    Article  CAS  PubMed  Google Scholar 

  82. Pangrsic T, Potokar M, Stenovec M, Kreft M, Fabbretti E, Nistri A, Pryazhnikov E, Khiroug L, Giniatullin R, Zorec R (2007) Exocytotic release of ATP from cultured astrocytes. J Biol Chem 282:28749–28758

    Article  CAS  PubMed  Google Scholar 

  83. Darby M, Kuzmiski JB, Panenka W, Feighan D, MacVicar BA (2003) ATP released from astrocytes during swelling activates chloride channels. J Neurophysiol 89:1870–1877

    Article  CAS  PubMed  Google Scholar 

  84. Suadicani SO, Brosnan CF, Scemes E (2006) P2X7 receptors mediate ATP release and amplification of astrocytic intercellular Ca2+ signaling. J Neurosci 26:1378–1385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Fields RD, Stevens B (2000) ATP: an extracellular signaling molecule between neurons and glia. Trends Neurosci 23:625–633

    Article  CAS  PubMed  Google Scholar 

  86. Kirischuk S, Moller T, Voitenko N, Kettenmann H, Verkhratsky A (1995) ATP-induced cytoplasmic calcium mobilization in Bergmann glial cells. J Neurosci 15:7861–7871

    CAS  PubMed  Google Scholar 

  87. Kirischuk S, Scherer J, Kettenmann H, Verkhratsky A (1995) Activation of P2-purinoreceptors triggered Ca2+ release from InsP3-sensitive internal stores in mammalian oligodendrocytes. J Physiol 483(Pt 1):41–57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Guthrie PB, Knappenberger J, Segal M, Bennett MV, Charles AC, Kater SB (1999) ATP released from astrocytes mediates glial calcium waves. J Neurosci 19:520–528

    CAS  PubMed  Google Scholar 

  89. Cotrina ML, Lin JH, Lopez-Garcia JC, Naus CC, Nedergaard M (2000) ATP-mediated glia signaling. J Neurosci 20:2835–2844

    CAS  PubMed  Google Scholar 

  90. Zhang JM, Wang HK, Ye CQ, Ge W, Chen Y, Jiang ZL, Wu CP, Poo MM, Duan S (2003) ATP released by astrocytes mediates glutamatergic activity-dependent heterosynaptic suppression. Neuron 40:971–982

    Article  CAS  PubMed  Google Scholar 

  91. Burnstock G (1978) A basis for distinguishing two types of purinergic receptor. In: Straub RW, Bolis L (eds) Cell membrane receptors for drugs and hormones: a multidisciplinary approach. Raven Press, New York, pp 107–118

    Google Scholar 

  92. Abbracchio MP, Burnstock G (1994) Purinoceptors: are there families of P2X and P2Y purinoceptors? Pharmacol Ther 64:445–475

    Article  CAS  PubMed  Google Scholar 

  93. North RA (2002) Molecular physiology of P2X receptors. Physiol Rev 82:1013–1067

    Article  CAS  PubMed  Google Scholar 

  94. Burnstock G, Verkhratsky A (2012) Purinergic signalling in the nervous system. Springer, Berlin

    Book  Google Scholar 

  95. Barrera NP, Ormond SJ, Henderson RM, Murrell-Lagnado RD, Edwardson JM (2005) Atomic force microscopy imaging demonstrates that P2X2 receptors are trimers but that P2X6 receptor subunits do not oligomerize. J Biol Chem 280:10759–10765

    Article  CAS  PubMed  Google Scholar 

  96. Egan TM, Samways DS, Li Z (2006) Biophysics of P2X receptors. Pflugers Arch 452:501–512

    Article  CAS  PubMed  Google Scholar 

  97. Roberts JA, Vial C, Digby HR, Agboh KC, Wen H, Atterbury-Thomas A, Evans RJ (2006) Molecular properties of P2X receptors. Pflugers Arch 452:486–500

    Article  CAS  PubMed  Google Scholar 

  98. Lalo U, Pankratov Y, Wichert SP, Rossner MJ, North RA, Kirchhoff F, Verkhratsky A (2008) P2X1 and P2X5 subunits form the functional P2X receptor in mouse cortical astrocytes. J Neurosci 28:5473–5480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Hamilton N, Vayro S, Kirchhoff F, Verkhratsky A, Robbins J, Gorecki DC, Butt AM (2008) Mechanisms of ATP- and glutamate-mediated calcium signaling in white matter astrocytes. Glia 56:734–749

    Article  PubMed  Google Scholar 

  100. Illes P, Verkhratsky A, Burnstock G, Franke H (2012) P2X receptors and their roles in astroglia in the central and peripheral nervous system. Neuroscientist 18:422–438

    Article  PubMed  CAS  Google Scholar 

  101. Ballerini P, Rathbone MP, Di Iorio P, Renzetti A, Giuliani P, D’Alimonte I, Trubiani O, Caciagli F, Ciccarelli R (1996) Rat astroglial P2Z (P2X7) receptors regulate intracellular calcium and purine release. NeuroReport 7:2533–2537

    Article  CAS  PubMed  Google Scholar 

  102. Duan S, Anderson CM, Keung EC, Chen Y, Swanson RA (2003) P2X7 receptor-mediated release of excitatory amino acids from astrocytes. J Neurosci 23:1320–1328

    CAS  PubMed  Google Scholar 

  103. Illes P, Ribeiro JA (2004) Neuronal P2 receptors of the central nervous system. Curr Top Med Chem 4:831–838

    Article  CAS  PubMed  Google Scholar 

  104. Verkhratsky A, Orkand RK, Kettenmann H (1998) Glial calcium: homeostasis and signaling function. Physiol Rev 78:99–141

    CAS  PubMed  Google Scholar 

  105. Cornell-Bell AH, Finkbeiner SM (1991) Ca2 + waves in astrocytes. Cell Calcium 12:185–204

    Article  CAS  PubMed  Google Scholar 

  106. Lechleiter J, Girard S, Peralta E, Clapham D (1991) Spiral calcium wave propagation and annihilation in Xenopus laevis oocytes. Science 252:123–126

    Article  CAS  PubMed  Google Scholar 

  107. Lechleiter JD, Clapham DE (1992) Molecular mechanisms of intracellular calcium excitability in X. laevis oocytes. Cell 69:283–294

    Article  CAS  PubMed  Google Scholar 

  108. Innocenti B, Parpura V, Haydon PG (2000) Imaging extracellular waves of glutamate during calcium signaling in cultured astrocytes. J Neurosci 20:1800–1808

    CAS  PubMed  Google Scholar 

  109. Strong AJ, Dardis R (2005) Depolarisation phenomena in traumatic and ischaemic brain injury. Adv Tech Stand Neurosurg 30:3–49

    CAS  PubMed  Google Scholar 

  110. Risher WC, Lee MR, Fomitcheva IV, Hess DC, Kirov SA (2011) Dibucaine mitigates spreading depolarization in human neocortical slices and prevents acute dendritic injury in the ischemic rodent neocortex. PLoS One 6:e22351. doi:10.1371/journal.pone.0022351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Edvinsson L, Krause DN (2002) Cerebral blood flow and metabolism. Lippincott Williams & Wilkins, Philadelphia

    Google Scholar 

  112. Risher WC, Ard D, Yuan J, Kirov SA (2010) Recurrent spontaneous spreading depolarizations facilitate acute dendritic injury in the ischemic penumbra. J Neurosci 30:9859–9868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Hinzman JM, DiNapoli VA, Mahoney EJ, Gerhardt GA, Hartings JA (2015) Spreading depolarizations mediate excitotoxicity in the development of acute cortical lesions. Exper Neurol 267:243–253

    Article  Google Scholar 

  114. Unterberg AW, Stover J, Kress B, Kiening KL (2004) Edema and brain trauma. Neuroscience 129:1021–1029

    Article  CAS  PubMed  Google Scholar 

  115. Dirnagl U, Iadecola C, Moskowitz MA (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 22:391–397

    Article  CAS  PubMed  Google Scholar 

  116. Watts LT, Lechleiter JD (2009) The impact of astrocyte mitochondrial metabolism on neuroprotection during aging. In: Parpura V, Haydon PG (eds) Astrocytes in (patho)physiology of the nervous system. Springer, New York, pp 569–590

    Chapter  Google Scholar 

  117. Sayre N, Chen Y, Sifuentes M, Stoveken B, Lechleiter J (2014) Purinergic receptor stimulation decreases ischemic brain damage by energizing astrocyte mitochondria. In: Parpura V, Schousboe A, Verkhratsky A (eds) Glutamate and ATP at the interface of metabolism and signaling in the brain. Springer, New York, pp 121–150

    Google Scholar 

  118. Stary C, Giffard R (2015) Advances in astrocyte-targeted approaches for stroke therapy: an emerging role for mitochondria and microRNAS. Neurochem Res 40:301–307

    Article  CAS  PubMed  Google Scholar 

  119. Bender AS, Schousboe A, Reichelt W, Norenberg MD (1998) Ionic mechanisms in glutamate-induced astrocyte swelling: role of K + influx. J Neurosci Res 52:307–321

    Article  CAS  PubMed  Google Scholar 

  120. Sonnewald U, Westergaard N, Schousboe A (1997) Glutamate transport and metabolism in astrocytes. Glia 21:56–63

    Article  CAS  PubMed  Google Scholar 

  121. Parpura V, Heneka MT, Montana V, Oliet SH, Schousboe A, Haydon PG, Stout RF Jr, Spray DC, Reichenbach A, Pannicke T, Pekny M, Pekna M, Zorec R, Verkhratsky A (2012) Glial cells in (patho)physiology. J Neurochem 121:4–27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Dreier JP (2011) The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease. Nat Med 17:439–447

    Article  CAS  PubMed  Google Scholar 

  123. Hartings JA, Rolli ML, Lu XC, Tortella FC (2003) Delayed secondary phase of peri-infarct depolarizations after focal cerebral ischemia: relation to infarct growth and neuroprotection. J Neurosci 23:11602–11610

    CAS  PubMed  Google Scholar 

  124. Benveniste H, Drejer J, Schousboe A, Diemer NH (1984) Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem 43:1369–1374

    Article  CAS  PubMed  Google Scholar 

  125. Silver IA, Erecińska M (1997) Energetic demands of the Na +/K + ATPase in mammalian astrocytes. Glia 21:35–45

    Article  CAS  PubMed  Google Scholar 

  126. Nehlig A, Coles JA (2007) Cellular pathways of energy metabolism in the brain: is glucose used by neurons or astrocytes? Glia 55:1238–1250

    Article  PubMed  Google Scholar 

  127. Hertz L, Peng L, Dienel GA (2007) Energy metabolism in astrocytes: high rate of oxidative metabolism and spatiotemporal dependence on glycolysis/glycogenolysis. J Cereb Blood Flow Metab 27:219–249

    Article  CAS  PubMed  Google Scholar 

  128. Lebon V, Petersen KF, Cline GW, Shen J, Mason GF, Dufour S, Behar KL, Shulman GI, Rothman DL (2002) 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. J Neurosci 22:1523–1531

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Blüml S, Moreno-Torres A, Shic F, Nguy CH, Ross BD (2002) Tricarboxylic acid cycle of glia in the in vivo human brain. NMR Biomed 15:1–5

    Article  PubMed  CAS  Google Scholar 

  130. Wu J, Holstein JD, Upadhyay G, Lin D-T, Conway S, Muller E, Lechleiter JD (2007) Purinergic Receptor-Stimulated IP3-Mediated Ca2 + Release Enhances Neuroprotection by Increasing Astrocyte Mitochondrial Metabolism during Aging. J Neurosci 27:6510–6520

    Article  CAS  PubMed  Google Scholar 

  131. Zheng W, Watts LT, Holstein DM, Wewer J, Lecheiter JD (2013) P2Y1R-initiated, IP3R-dependent stimulation of astrocyte mitochondrial metabolism reduces and partially reverses ischemic neuronal damage in mouse. J Cereb Blood Flow Metab 33:600–611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Zheng W, Watts LT, Holstein DM, Prajapati SI, Keller C, Grass EH, Walter CA, Lechleiter JD (2010) Purinergic receptor stimulation reduces cytotoxic edema and brain infarcts in mouse induced by photothrombosis by energizing glial mitochondria. PLoS One 5:e14401. doi:10.1371/journal.pone.0014401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Mattson MP, Rychlik B (1990) Glia protect hippocampal neurons against excitatory amino acid-induced degeneration: involvement of fibroblast growth factor. Int J Dev Neurosci 8:399–415

    Article  CAS  PubMed  Google Scholar 

  134. Largo CCP, Somjen GG, Martin del Rio R, Herreras O (1996) The effect of depressing glial function in rat brain in situ on ion homeostasis, synaptic transmission, and neuron survival. J Neurosci 16:1219–1229

    CAS  PubMed  Google Scholar 

  135. Largo C, Cuevas P, Herreras O (1996) Is glia disfunction the initial cause of neuronal death in ischemic penumbra? Neurol Res 18:445–448

    Article  CAS  PubMed  Google Scholar 

  136. Burnstock G (2013) Introduction to purinergic signalling in the brain. Adv Exp Med Biol 986:1–12

    Article  CAS  PubMed  Google Scholar 

  137. Abbracchio MP, Burnstock G, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C, Knight GE, Fumagalli M, Gachet C, Jacobson KA, Weisman GA (2006) International Union of Pharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy. Pharmacol Rev 58:281–341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Abbracchio MP, Burnstock G, Verkhratsky A, Zimmermann H (2009) Purinergic signalling in the nervous system: an overview. Trends Neurosci 32:19–29

    Article  CAS  PubMed  Google Scholar 

  139. Franke H, Krugel U, Grosche J, Heine C, Hartig W, Allgaier C, Illes P (2004) P2Y receptor expression on astrocytes in the nucleus accumbens of rats. Neuroscience 127:431–441

    Article  CAS  PubMed  Google Scholar 

  140. Butt AM (2011) ATP: a ubiquitous gliotransmitter integrating neuron–glial networks. Semin Cell Dev Biol 22:205–213

    Article  CAS  PubMed  Google Scholar 

  141. Cotrina ML, Lin JHC, Nedergaard M (1998) Cytoskeletal assembly and ATP release regulate astrocytic calcium signaling. J Neurosci 18:8794–8804

    CAS  PubMed  Google Scholar 

  142. Verkhratsky A, Rodriguez JJ, Parpura V (2012) Calcium signalling in astroglia. Mol Cell Endocrinol 353:45–56

    Article  CAS  PubMed  Google Scholar 

  143. Watson BD, Dietrich WD, Busto R, Wachtel MS, Ginsberg MD (1985) Induction of reproducible brain infarction by photochemically initiated thrombosis. Annal Neurol 17:497–504

    Article  CAS  PubMed  Google Scholar 

  144. Liang D, Bhatta S, Gerzanich V, Simard JM (2007) Cytotoxic edema: mechanisms of pathological cell swelling. Neurosurg Focus 22:E2

    Article  PubMed  PubMed Central  Google Scholar 

  145. Zheng W, Talley Watts L, Holstein DM, Wewer J, Lechleiter JD (2013) P2Y1R-initiated, IP3R-dependent stimulation of astrocyte mitochondrial metabolism reduces and partially reverses ischemic neuronal damage in mouse. J Cereb Blood Flow Metab 33:600–611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. McKenna MC, Sonnewald U, Huang X, Stevenson J, Zielke HR (1996) Exogenous glutamate concentration regulates the metabolic fate of glutamate in astrocytes. J Neurochem 66:386–393

    Article  CAS  PubMed  Google Scholar 

  147. Sonnewald U, Westergaard N, Petersen SB, Unsgard G, Schousboe A (1993) Metabolism of [U-13C]glutamate in astrocytes studied by 13C NMR spectroscopy: incorporation of more label into lactate than into glutamine demonstrates the importance of the tricarboxylic acid cycle. J Neurochem 61:1179–1182

    Article  CAS  PubMed  Google Scholar 

  148. Frigerio F, Karaca M, De Roo M, Mlynárik V, Skytt DM, Carobbio S, Pajęcka K, Waagepetersen HS, Gruetter R, Muller D, Maechler P (2012) Deletion of glutamate dehydrogenase 1 (Glud1) in the central nervous system affects glutamate handling without altering synaptic transmission. J Neurochem 123:342–348

    Article  CAS  PubMed  Google Scholar 

  149. Whitelaw BS, Robinson MB (2013) Inhibitors of glutamate dehydrogenase block sodium-dependent glutamate uptake in rat brain membranes. Front Endocrinol 4:123. doi:10.3389/fendo.2013.00123

    Article  Google Scholar 

  150. Fabricius M, Fuhr S, Bhatia R, Boutelle M, Hashemi P, Strong AJ, Lauritzen M (2006) Cortical spreading depression and peri-infarct depolarization in acutely injured human cerebral cortex. Brain 129:778–790

    Article  PubMed  Google Scholar 

  151. Zador Z, Stiver S, Wang V, Manley GT (2009) Role of aquaporin-4 in cerebral edema and stroke. Handb Exp Pharmacol 190:159–170

    Article  CAS  Google Scholar 

  152. Thrane AS, Rangroo Thrane V, Nedergaard M (2014) Drowning stars: reassessing the role of astrocytes in brain edema. Trends Neurosci 37:620–628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Stys PK, Waxman SG, Ransom BR (1992) Effects of temperature on evoked electrical activity and anoxic injury in CNS white matter. J Cereb Blood Flow Metabol 12:977–986

    Article  CAS  Google Scholar 

  154. Fern RJ, Hahm MS, Lu HK, Liu LP, Gorelick FS, Barrett PQ (1995) Ca2+/calmodulin-dependent protein kinase II activation and regulation of adrenal glomerulosa Ca2+ signaling. Am J Physiol 269:F751–F760

    CAS  PubMed  Google Scholar 

  155. Wolf JA, Stys PK, Lusardi T, Meaney D, Smith DH (2001) Traumatic axonal injury induces calcium influx modulated by tetrodotoxin-sensitive sodium channels. J Neurosci 21:1923–1930

    CAS  PubMed  Google Scholar 

  156. Ouardouz M, Nikolaeva MA, Coderre E, Zamponi GW, McRory JE, Trapp BD, Yin X, Wang W, Woulfe J, Stys PK (2003) Depolarization-induced Ca2 + release in ischemic spinal cord white matter involves L-type Ca2 + channel activation of ryanodine receptors. Neuron 40:53–63

    Article  CAS  PubMed  Google Scholar 

  157. Underhill SM, Goldberg MP (2007) Hypoxic injury of isolated axons is independent of ionotropic glutamate receptors. Neurobiol Dis 25:284–290

    Article  CAS  PubMed  Google Scholar 

  158. Tekkok SB, Ye Z, Ransom BR (2007) Excitotoxic Mechanisms of Ischemic Injury in Myelinated White Matter. J Cereb Blood Flow Metab 27:1540–1552

    Article  PubMed  CAS  Google Scholar 

  159. Matute C, Sanchez-Gomez MV, Martinez-Millan L, Miledi R (1997) Glutamate receptor-mediated toxicity in optic nerve oligodendrocytes. Proc Natl Acad Sci USA 94:8830–8835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. McDonald JW, Althomsons SP, Hyrc KL, Choi DW, Goldberg MP (1998) Oligodendrocytes from forebrain are highly vulnerable to AMPA/kainate receptor-mediated excitotoxicity. Nat Med 4:291–297

    Article  CAS  PubMed  Google Scholar 

  161. Li S, Mealing GA, Morley P, Stys PK (1999) Novel injury mechanism in anoxia and trauma of spinal cord white matter: glutamate release via reverse Na+-dependent glutamate transport. J Neurosci 19:RC 1–9

  162. Rosenberg LJ, Teng YD, Wrathall JR (1999) 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline reduces glial loss and acute white matter pathology after experimental spinal cord contusion. J Neurosci 19:464–475

    CAS  PubMed  Google Scholar 

  163. Sanchez-Gomez MV, Matute C (1999) AMPA and kainate receptors each mediate excitotoxicity in oligodendroglial cultures. Neurobiol Dis 6:475–485

    Article  CAS  PubMed  Google Scholar 

  164. Tekkok SB, Goldberg MP (2001) Ampa/kainate receptor activation mediates hypoxic oligodendrocyte death and axonal injury in cerebral white matter. J Neurosci 21:4237–4248

    CAS  PubMed  Google Scholar 

  165. Alberdi E, Sanchez-Gomez MV, Marino A, Matute C (2002) Ca2+ influx through AMPA or kainate receptors alone is sufficient to initiate excitotoxicity in cultured oligodendrocytes. Neurobiol Dis 9:234–243

    Article  CAS  PubMed  Google Scholar 

  166. Li S, Stys PK (2000) Mechanisms of ionotropic glutamate receptor-mediated excitotoxicity in isolated spinal cord white matter. J Neurosci 20:1190–1198

    CAS  PubMed  Google Scholar 

  167. Baltan S (2015) Age-specific localization of NMDA receptors on oligodendrocytes dictates axon function recovery after ischemia. Neuropharmacology (in press). doi:10.1016/j.neuropharm.2015.1009.1015

  168. Baltan S, Besancon EF, Mbow B, Ye Z, Hamner MA, Ransom BR (2008) White matter vulnerability to ischemic injury increases with age because of enhanced excitotoxicity. J Neurosci 28:1479–1489

    Article  CAS  PubMed  Google Scholar 

  169. Oka A, Belliveau MJ, Rosenberg PA, Volpe JJ (1993) Vulnerability of oligodendroglia to glutamate: pharmacology, mechanisms, and prevention. J Neurosci 13:1441–1453

    CAS  PubMed  Google Scholar 

  170. Chang DT, Honick AS, Reynolds IJ (2006) Mitochondrial trafficking to synapses in cultured primary cortical neurons. J Neurosci 26:7035–7045

    Article  CAS  PubMed  Google Scholar 

  171. Chang DT, Reynolds IJ (2006) Mitochondrial trafficking and morphology in healthy and injured neurons. Prog Neurobiol 80:241–268

    Article  CAS  PubMed  Google Scholar 

  172. Chang DT, Reynolds IJ (2006) Differences in mitochondrial movement and morphology in young and mature primary cortical neurons in culture. Neuroscience 141:727–736

    Article  CAS  PubMed  Google Scholar 

  173. Baltan S (2014) Excitotoxicity and mitochondrial dysfunction underlie age-dependent ischemic white matter injury. Adv Neurobiol 11:151–170

    Article  PubMed  Google Scholar 

  174. Baltan S, Morrison RS, Murphy SP (2013) Novel protective effects of histone deacetylase inhibition on stroke and white matter ischemic injury. Neurotherapeutics 10:798–807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Baltan S, Murphy SP, Danilov CA, Bachleda A, Morrison RS (2011) Histone deacetylase inhibitors preserve white matter structure and function during ischemia by conserving ATP and reducing excitotoxicity. J Neurosci 31:3990–3999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Baltan S (2012) Histone Deacetylase inhibitors preserve function in aging axons. J Neurochem 123(Suppl 2):108–115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Misgeld T, Kerschensteiner M, Bareyre FM, Burgess RW, Lichtman JW (2007) Imaging axonal transport of mitochondria in vivo. Nat Methods 4:559–561

    Article  CAS  PubMed  Google Scholar 

  178. Matute C, Alberdi E, Domercq M, Perez-Cerda F, Perez-Samartin A, Sanchez-Gomez MV (2001) The link between excitotoxic oligodendroglial death and demyelinating diseases. Trends Neurosci 24:224–230

    Article  CAS  PubMed  Google Scholar 

  179. Ouardouz M, Malek S, Coderre E, Stys PK (2006) Complex interplay between glutamate receptors and intracellular Ca2+ stores during ischaemia in rat spinal cord white matter. J Physiol 577:191–204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Szabadkai G, Duchen MR (2008) Mitochondria: the hub of cellular Ca2+ signaling. Physiology 23:84–94

    Article  CAS  PubMed  Google Scholar 

  181. Chen H, McCaffery JM, Chan DC (2007) Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell 130:548–562

    Article  CAS  PubMed  Google Scholar 

  182. Chang CC, Liao YS, Lin YL, Chen RM (2006) Nitric oxide protects osteoblasts from oxidative stress-induced apoptotic insults via a mitochondria-dependent mechanism. J Orthopaedic Res 24:1917–1925

    Article  CAS  Google Scholar 

  183. Toescu EC (2005) Normal brain ageing: models and mechanisms. Philos Trans R Soc Lond B Biol Sci 360:2347–2354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Baltan S, Stahon K, Bastian C, Kidd G, Brunet S (2014) Age-dependent alterations in axon-myelin interactions, mitochondrial dynamics and Ca2+ homeostasis underlie the increased vulnerability of aging axons to ischemia. Soc Neurosci Abstracts 310.04/J4

  185. Murphy SP, Lee RJ, McClean ME, Pemberton HE, Uo T, Morrison RS, Bastian C, Baltan S (2014) MS-275, a class I histone deacetylase inhibitor, protects the p53-deficient mouse against ischemic injury. J Neurochem 129:509–515

    Article  CAS  PubMed  Google Scholar 

  186. Endres M, Meisel A, Biniszkiewicz D, Namura S, Prass K, Ruscher K, Lipski A, Jaenisch R, Moskowitz MA, Dirnagl U (2000) DNA methyltransferase contributes to delayed ischemic brain injury. J Neurosci 20:3175–3181

    CAS  PubMed  Google Scholar 

  187. Yildirim F, Gertz K, Kronenberg G, Harms C, Fink KB, Meisel A, Endres M (2008) Inhibition of histone deacetylation protects wildtype but not gelsolin-deficient mice from ischemic brain injury. Exp Neurol 210:531–542

    Article  CAS  PubMed  Google Scholar 

  188. Ren M, Leng Y, Jeong M, Leeds PR, Chuang DM (2004) Valproic acid reduces brain damage induced by transient focal cerebral ischemia in rats: potential roles of histone deacetylase inhibition and heat shock protein induction. J Neurochem 89:1358–1367

    Article  CAS  PubMed  Google Scholar 

  189. Langley B, D’Annibale MA, Suh K, Ayoub I, Tolhurst A, Bastan B, Yang L, Ko B, Fisher M, Cho S, Beal MF, Ratan RR (2008) Pulse inhibition of histone deacetylases induces complete resistance to oxidative death in cortical neurons without toxicity and reveals a role for cytoplasmic p21(waf1/cip1) in cell cycle-independent neuroprotection. J Neurosci 28:163–176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Kim HJ, Rowe M, Ren M, Hong JS, Chen PS, Chuang DM (2007) Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: multiple mechanisms of action. J Pharmacol Exp Ther 321:892–901

    Article  CAS  PubMed  Google Scholar 

  191. Faraco G, Pancani T, Formentini L, Mascagni P, Fossati G, Leoni F, Moroni F, Chiarugi A (2006) Pharmacological inhibition of histone deacetylases by suberoylanilide hydroxamic acid specifically alters gene expression and reduces ischemic injury in the mouse brain. Mol Pharmacol 70:1876–1884

    Article  CAS  PubMed  Google Scholar 

  192. Baltan S, Bachleda A, Morrison RS, Murphy SP (2011) Expression of Histone Deacetylases in Cellular Compartments of the Mouse Brain and the Effects of Ischemia. Transl Stroke Res 2:411–423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Nissen C, Schousboe A (1979) Activity and isoenzyme pattern of lactate dehydrogenase in astroblasts cultured from brains of newborn mice. J Neurochem 32:1787–1792

    Article  CAS  PubMed  Google Scholar 

  194. Lauritzen KH, Morland C, Puchades M, Holm-Hansen S, Hagelin EM, Lauritzen F, Attramadal H, Storm-Mathisen J, Gjedde A, Bergersen LH (2014) Lactate receptor sites link neurotransmission, neurovascular coupling, and brain energy metabolism. Cereb Cortex 24:2784–2795

    Article  PubMed  Google Scholar 

  195. Verkhratsky A, Kirchhoff F (2007) NMDA Receptors in glia. Neuroscientist 13:28–37

    CAS  PubMed  Google Scholar 

  196. Walz W, Gimpl G, Ohlemeyer C, Kettenmann H (1994) Extracellular ATP-induced currents in astrocytes: involvement of a cation channel. J Neurosci Res 38:12–18

    Article  CAS  PubMed  Google Scholar 

  197. Franke H, Grosche J, Schadlich H, Krugel U, Allgaier C, Illes P (2001) P2X receptor expression on astrocytes in the nucleus accumbens of rats. Neuroscience 108:421–429

    Article  CAS  PubMed  Google Scholar 

  198. Kukley M, Barden JA, Steinhauser C, Jabs R (2001) Distribution of P2X receptors on astrocytes in juvenile rat hippocampus. Glia 36:11–21

    Article  CAS  PubMed  Google Scholar 

  199. Sun SH, Lin LB, Hung AC, Kuo JS (1999) ATP-stimulated Ca2+ influx and phospholipase D activities of a rat brain-derived type-2 astrocyte cell line, RBA-2, are mediated through P2X7 receptors. J Neurochem 73:334–343

    Article  CAS  PubMed  Google Scholar 

  200. Chakfe Y, Seguin R, Antel JP, Morissette C, Malo D, Henderson D, Seguela P (2002) ADP and AMP induce interleukin-1beta release from microglial cells through activation of ATP-primed P2X7 receptor channels. J Neurosci 22:3061–3069

    PubMed  Google Scholar 

  201. Verkhratsky A, Kettenmann H (1996) Calcium signalling in glial cells. Trends Neurosci 19:346–352

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Authors’ research was supported by Alzheimer’s Research Trust (UK) Programme Grant (ART/PG2004A/1 to A.V.), William and Ella Owens Medical Research Foundation (JDL), and by the National Institutes of Health (NIH), The Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD078678 to V.P), The National Institute of Aging (01AG033720 to S.B.) and The National Institute of Neurological Disorders and Stroke (R41NS093756 to JDS).

Author information

Author notes

    Authors and Affiliations

    1. Department of Neurobiology, Center for Glial Biology in Medicine, Atomic Force Microscopy and Nanotechnology Laboratories, Civitan International Research Center, Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, 1719 6th Avenue South, CIRC 429, Birmingham, AL, 35294, USA

      Vladimir Parpura

    2. Department of Cellular and Structural Biology, University of Texas Health Science Center San Antonio, San Antonio, TX, 78229, USA

      Elizabeth S. Fisher & James D. Lechleiter

    3. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark

      Arne Schousboe & Helle S. Waagepetersen

    4. Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH, 44195, USA

      Sylvain Brunet & Selva Baltan

    5. Faculty of Life Sciences, The University of Manchester, Manchester, M13 9PT, UK

      Alexei Verkhratsky

    6. Achucarro Center for Neuroscience, IKERBASQUE, Basque Foundation for Science, 48011, Bilbao, Spain

      Alexei Verkhratsky

    7. Department of Neurosciences, University of the Basque Country UPV/EHU, 48940, Leioa, Spain

      Alexei Verkhratsky

    Authors
    1. Vladimir Parpura
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Elizabeth S. Fisher
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. James D. Lechleiter
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Arne Schousboe
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Helle S. Waagepetersen
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Sylvain Brunet
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Selva Baltan
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Alexei Verkhratsky
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Vladimir Parpura.

    Additional information

    All authors have contributed equally to this work and are available for correspondence.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Parpura, V., Fisher, E.S., Lechleiter, J.D. et al. Glutamate and ATP at the Interface Between Signaling and Metabolism in Astroglia: Examples from Pathology. Neurochem Res 42, 19–34 (2017). https://doi.org/10.1007/s11064-016-1848-6

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s11064-016-1848-6

    Keywords

    Search

    Navigation