Skip to main content

Advertisement

Log in

Why are Astrocytes Important?

  • Overview
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Astrocytes, which populate the grey and white mater of the brain and the spinal cord are highly heterogeneous in their morphology and function. These cells are primarily responsible for homeostasis of the central nervous system (CNS). Most central synapses are surrounded by exceedingly thin astroglial perisynaptic processes, which act as “astroglial cradle” critical for genesis, maturation and maintenance of synaptic connectivity. The perisynaptic glial processes are densely packed with numerous transporters, which provide for homeostasis of ions and neurotransmitters in the synaptic cleft, for local metabolic support and for release of astroglial derived scavengers of reactive oxygen species. Through perivascular processes astrocytes contribute to blood–brain barrier and form “glymphatic” drainage system of the CNS. Furthermore astrocytes are indispensible for glutamatergic and γ-aminobutyrate-ergic synaptic transmission being the supplier of neurotransmitters precursor glutamine via an astrocytic/neuronal cycle. Pathogenesis of many neurological disorders, including neuropsychiatric and neurodegenerative diseases is defined by loss of homeostatic function (astroglial asthenia) or remodelling of astroglial homoeostatic capabilities. Astroglial cells further contribute to neuropathologies through mounting complex defensive programme generally known as reactive astrogliosis.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Nicholls JG, Kuffler SW (1965) Na and K content of glial cells and neurons determined by flame photometry in the central nervous system of the leech. J Neurophysiol 28:519–525

    CAS  PubMed  Google Scholar 

  2. Hyden H, Lange PW (1965) Rhythmic enzyme changes in neurons and glia during sleep. Science 149:654–656

    CAS  PubMed  Google Scholar 

  3. Hyden H, Lange PW (1965) The steady state and sndogenous sespiration in neuron and glia. Acta Physiol Scand 64:6–14

    CAS  PubMed  Google Scholar 

  4. VanHarreveld A, Crowell J, Malhotra SK (1965) A study of extracellular space in central nervous tissue by freeze-substitution. J Cell Biol 25:117–137

    CAS  PubMed  Google Scholar 

  5. van den Berg CJ, Garfinkel D (1971) A stimulation study of brain compartments. Metabolism of glutamate and related substances in mouse brain. Biochem J 123:211–218

    PubMed  Google Scholar 

  6. Benjamin AM, Quastel JH (1972) Locations of amino acids in brain slices from the rat. Tetrodotoxin-sensitive release of amino acids. Biochem J 128:631–646

    PubMed Central  CAS  PubMed  Google Scholar 

  7. Norenberg MD, Lapham LW, Eastland MW, May AG (1972) Division of protoplasmic astrocytes in acute experimental hepatic encephalopathy. An electron microscopic study. Am J Pathol 67:403–411

    PubMed Central  CAS  PubMed  Google Scholar 

  8. Martinez-Hernandez A, Bell KP, Norenberg MD (1977) Glutamine synthetase: glial localization in brain. Science 195:1356–1358

    CAS  PubMed  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

    CAS  PubMed  Google Scholar 

  10. Sibson NR, Dhankhar A, Mason GF, Rothman DL, Behar KL, Shulman RG (1998) Stoichiometric coupling of brain glucose metabolism and glutamatergic neuronal activity. Proc Natl Acad Sci USA 95:316–321

    PubMed Central  CAS  PubMed  Google Scholar 

  11. Hyder F, Fulbright RK, Shulman RG, Rothman DL (2013) Glutamatergic function in the resting awake human brain is supported by uniformly high oxidative energy. J Cereb Blood Flow Metab 33:339–347

    PubMed Central  CAS  PubMed  Google Scholar 

  12. Bringmann A, Grosche A, Pannicke T, Reichenbach A (2013) GABA and glutamate uptake and metabolism in retinal glial (Muller) cells. Front Endocrinol 4:48

    CAS  Google Scholar 

  13. Schousboe A, Bak LK, Waagepetersen HS (2013) Astrocytic control of biosynthesis and turnover of the neurotransmitters glutamate and GABA. Front Endocrinol 4:102

    Google Scholar 

  14. Pardo B, Rodrigues TB, Contreras L, Garzon M, Llorente-Folch I, Kobayashi K, Saheki T, Cerdan S, Satrustegui J (2011) Brain glutamine synthesis requires neuronal-born aspartate as amino donor for glial glutamate formation. J Cereb Blood Flow Metab 31:90–101

    PubMed Central  CAS  PubMed  Google Scholar 

  15. Pardo B, Contreras L, Satrustegui J (2013) Synthesis of glial glutamate and glutamine in young mice requires aspartate provided by the neuronal mitochondrial aspartate–glutamate carrier aralar/AGC1. Front Endocrinol 4:149

    Google Scholar 

  16. Cooper AJ (2013) Quantitative analysis of neurotransmitter pathways under steady state conditions—a perspective. Front Endocrinol 4:179

    Google Scholar 

  17. Hertz L (2013) The Glutamate-Glutamine (GABA) Cycle: importance of Late Postnatal Development and Potential Reciprocal Interactions between Biosynthesis and Degradation. Front Endocrinol 4:59

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  19. 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

    CAS  PubMed  Google Scholar 

  20. Rothman DL, De Feyter HM, de Graaf RA, Mason GF, Behar KL (2011) 13C MRS studies of neuroenergetics and neurotransmitter cycling in humans. NMR Biomed 24:943–957

    PubMed Central  CAS  PubMed  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

    PubMed Central  CAS  PubMed  Google Scholar 

  22. 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

    PubMed Central  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

    PubMed Central  CAS  PubMed  Google Scholar 

  24. McKenna MC (2012) Substrate competition studies demonstrate oxidative metabolism of glucose, glutamate, glutamine, lactate and 3-hydroxybutyrate in cortical astrocytes from rat brain. Neurochem Res 37:2613–2626

    PubMed Central  CAS  PubMed  Google Scholar 

  25. McKenna MC (2013) Glutamate pays its own way in astrocytes. Front Endocrinol 4:191

    Google Scholar 

  26. Whitelaw BS, Robinson MB (2013) Inhibitors of glutamate dehydrogenase block sodium-dependent glutamate uptake in rat brain membranes. Front Endocrinol 4:123

    Google Scholar 

  27. Barnett NL, Pow DV, Robinson SR (2000) Inhibition of Muller cell glutamine synthetase rapidly impairs the retinal response to light. Glia 30:64–73

    CAS  PubMed  Google Scholar 

  28. Ola MS, Hosoya K, LaNoue KF (2011) Regulation of glutamate metabolism by hydrocortisone and branched chain keto acids in cultured rat retinal Muller cells (TR-MUL). Neurochem Int 59:656–663

    CAS  PubMed  Google Scholar 

  29. Gorovits R, Avidan N, Avisar N, Shaked I, Vardimon L (1997) Glutamine synthetase protects against neuronal degeneration in injured retinal tissue. Proc Natl Acad Sci USA 94:7024–7029

    PubMed Central  CAS  PubMed  Google Scholar 

  30. Nissen-Meyer LS, Chaudhry FA (2013) Protein kinase c phosphorylates the system N glutamine transporter SN1 (Slc38a3) and regulates its membrane trafficking and degradation. Front Endocrinol 4:138

    Google Scholar 

  31. Bak LK, Sickmann HM, Schousboe A, Waagepetersen HS (2005) Activity of the lactate-alanine shuttle is independent of glutamate-glutamine cycle activity in cerebellar neuronal-astrocytic cultures. J Neurosci Res 79:88–96

    CAS  PubMed  Google Scholar 

  32. Rothman DL, De Feyter HM, Maciejewski PK, Behar KL (2012) Is there in vivo evidence for amino acid shuttles carrying ammonia from neurons to astrocytes? Neurochem Res 37:2597–2612

    PubMed Central  CAS  PubMed  Google Scholar 

  33. Calvetti D, Somersalo E (2013) Quantitative in silico analysis of neurotransmitter pathways under steady state conditions. Front Endocrinol 4:137

    Google Scholar 

  34. Nagaraja TN, Brookes N (1998) Intracellular acidification induced by passive and active transport of ammonium ions in astrocytes. Am J Physiol 274:C883–C891

    CAS  PubMed  Google Scholar 

  35. Palaiologos G, Hertz L, Schousboe A (1989) Role of aspartate aminotransferase and mitochondrial dicarboxylate transport for release of endogenously and exogenously supplied neurotransmitter in glutamatergic neurons. Neurochem Res 14:359–366

    CAS  PubMed  Google Scholar 

  36. Bak LK, Zieminska E, Waagepetersen HS, Schousboe A, Albrecht J (2008) Metabolism of [U-13C]glutamine and [U-13C]glutamate in isolated rat brain mitochondria suggests functional phosphate-activated glutaminase activity in matrix. Neurochem Res 33:273–278

    CAS  PubMed  Google Scholar 

  37. Lund TM, Risa O, Sonnewald U, Schousboe A, Waagepetersen HS (2009) Availability of neurotransmitter glutamate is diminished when beta-hydroxybutyrate replaces glucose in cultured neurons. J Neurochem 110:80–91

    CAS  PubMed  Google Scholar 

  38. Sonnewald U, McKenna M (2002) Metabolic compartmentation in cortical synaptosomes: influence of glucose and preferential incorporation of endogenous glutamate into GABA. Neurochem Res 27:43–50

    CAS  PubMed  Google Scholar 

  39. Chowdhury GM, Jiang L, Rothman DL, Behar KL (2014) The contribution of ketone bodies to basal and activity-dependent neuronal oxidation in vivo. J Cereb Blood Flow Metab 34:1233–1242

  40. Bjornsen LP, Hadera MG, Zhou Y, Danbolt NC, Sonnewald U (2014) The GLT-1 (EAAT2; slc1a2) glutamate transporter is essential for glutamate homeostasis in the neocortex of the mouse. J Neurochem 128:641–649

    CAS  PubMed  Google Scholar 

  41. Zhou Y, Danbolt NC (2013) GABA and glutamate transporters in brain. Front Endocrinol 4:165

    Google Scholar 

  42. Cruz NF, Ball KK, Dienel GA (2007) Functional imaging of focal brain activation in conscious rats: impact of [14C]glucose metabolite spreading and release. J Neurosci Res 85:3254–3266

    CAS  PubMed  Google Scholar 

  43. Balazs R (1965) Control of glutamate oxidation in brain and liver mitochondrial systems. Biochem J 95:497–508

    PubMed Central  CAS  PubMed  Google Scholar 

  44. Frigerio F, Karaca M, De Roo M, Mlynarik V, Skytt DM, Carobbio S, Pajecka 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

    CAS  PubMed  Google Scholar 

  45. Kurz GM, Wiesinger H, Hamprecht B (1993) Purification of cytosolic malic enzyme from bovine brain, generation of monoclonal antibodies, and immunocytochemical localization of the enzyme in glial cells of neural primary cultures. J Neurochem 60:1467–1474

    CAS  PubMed  Google Scholar 

  46. 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

    CAS  PubMed  Google Scholar 

  47. Patel AB, de Graaf RA, Mason GF, Rothman DL, Shulman RG, Behar KL (2005) The contribution of GABA to glutamate/glutamine cycling and energy metabolism in the rat cortex in vivo. Proc Natl Acad Sci USA 102:5588–5593

    PubMed Central  CAS  PubMed  Google Scholar 

  48. Yogeeswari P, Sriram D, Vaigundaragavendran J (2005) The GABA shunt: an attractive and potential therapeutic target in the treatment of epileptic disorders. Curr Drug Metab 6:127–139

    CAS  PubMed  Google Scholar 

  49. Wong E, Schousboe A, Saito K, Wu JY, Roberts E (1974) Immunochemical studies of brain glutamate decarboxylase and GABA-transaminase of six inbred strains of mice. Brain Res 68:133–142

    CAS  PubMed  Google Scholar 

  50. Schousboe I, Bro B, Schousboe A (1977) Intramitochondrial localization of the 4-aminobutyrate-2-oxoglutarate transaminase from ox brain. Biochem J 162:303–307

    PubMed Central  CAS  PubMed  Google Scholar 

  51. McKenna MC, Sonnewald U (2005) GABA alters the metabolic fate of U−13Cglutamate in cultured cortical astrocytes. J Neurosci Res 79:81–87

    CAS  PubMed  Google Scholar 

  52. Schousboe A (1972) Development of potassium effects on ion concentrations and indicator spaces in rat brain-cortex slices during postnatal ontogenesis. Exp Brain Res 15:521–531

    CAS  PubMed  Google Scholar 

  53. Roessmann U, Gambetti P (1986) Astrocytes in the developing human brain. An immunohistochemical study. Acta Neuropathol 70:308–313

    CAS  PubMed  Google Scholar 

  54. Marn-Padilla M (2011) The human brain. Springer, Berlin

    Google Scholar 

  55. Rothman DL, Behar KL, Hyder F, Shulman RG (2003) In vivo NMR studies of the glutamate neurotransmitter flux and neuroenergetics: implications for brain function. Annu Rev Physiol 65:401–427

    CAS  PubMed  Google Scholar 

  56. Gruetter R, Seaquist ER, Ugurbil K (2001) A mathematical model of compartmentalized neurotransmitter metabolism in the human brain. Am J Physiol 281:E100–E112

    CAS  Google Scholar 

  57. Lanz B, Uffmann KT, Wyss M, Weber B, Buck A, Gruetter R (2012) A two-compartment mathematical model of neuroglial metabolism using [1-11C] acetate. J Cereb Blood Flow Metab 32:548–559

    PubMed Central  CAS  PubMed  Google Scholar 

  58. Miller FD, Gauthier AS (2007) Timing is everything: making neurons versus glia in the developing cortex. Neuron 54:357–369

    CAS  PubMed  Google Scholar 

  59. Mauch DH, Nagler K, Schumacher S, Goritz C, Muller EC, Otto A, Pfrieger FW (2001) CNS synaptogenesis promoted by glia-derived cholesterol. Science 294:1354–1357

    CAS  PubMed  Google Scholar 

  60. Pfrieger FW (2010) Role of glial cells in the formation and maintenance of synapses. Brain Res Rev 63:39–46

    CAS  PubMed  Google Scholar 

  61. Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 29:3974–3980

    CAS  PubMed  Google Scholar 

  62. Araque A, Parpura V, Sanzgiri RP, Haydon PG (1999) Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 22:208–215

    CAS  PubMed  Google Scholar 

  63. De Leo JA, Tawfik VL, LaCroix-Fralish ML (2006) The tetrapartite synapse: path to CNS sensitization and chronic pain. Pain 122:17–21

    PubMed  Google Scholar 

  64. Dityatev A, Rusakov DA (2011) Molecular signals of plasticity at the tetrapartite synapse. Curr Opin Neurobiol 21:353–359

    PubMed Central  CAS  PubMed  Google Scholar 

  65. Verkhratsky A, Nedergaard M (2014) Astroglial cradle in the life of the synapse. Phil Trans Roy Soc Ser B (in press)

  66. Witcher MR, Kirov SA, Harris KM (2007) Plasticity of perisynaptic astroglia during synaptogenesis in the mature rat hippocampus. Glia 55:13–23

    PubMed  Google Scholar 

  67. Reichenbach A, Derouiche A, Kirchhoff F (2010) Morphology and dynamics of perisynaptic glia. Brain Res Rev 63:11–25

    PubMed  Google Scholar 

  68. Wolff JR, Chao TI (2004) Cytoarchitectonics of non-neuronal cells in the nervous system. In: Hertz L (ed) Non-neuronal cells of the nervous system: function and dysfunction. Elsevier, Amsterdam, pp 1–51

    Google Scholar 

  69. Patrushev I, Gavrilov N, Turlapov V, Semyanov A (2013) Subcellular location of astrocytic calcium stores favors extrasynaptic neuron–astrocyte communication. Cell Calcium 54:343–349

    CAS  PubMed  Google Scholar 

  70. Grosche J, Kettenmann H, Reichenbach A (2002) Bergmann glial cells form distinct morphological structures to interact with cerebellar neurons. J Neurosci Res 68:138–149

    CAS  PubMed  Google Scholar 

  71. Kirischuk S, Parpura V, Verkhratsky A (2012) Sodium dynamics: another key to astroglial excitability? Trends Neurosci 35:497–506

    CAS  PubMed  Google Scholar 

  72. Parpura V, Verkhratsky A (2012) Homeostatic function of astrocytes: Ca2+ and Na+ signalling. Transl Neurosci 3:334–344

    PubMed Central  PubMed  Google Scholar 

  73. Oliet SH, Bonfardin VD (2010) Morphological plasticity of the rat supraoptic nucleus–cellular consequences. Eur J Neurosci 32:1989–1994

    PubMed  Google Scholar 

  74. Hirrlinger J, Hulsmann S, Kirchhoff F (2004) Astroglial processes show spontaneous motility at active synaptic terminals in situ. Eur J Neurosci 20:2235–2239

    PubMed  Google Scholar 

  75. Nedergaard M, Verkhratsky A (2012) Artifact versus reality—how astrocytes contribute to synaptic events. Glia 60:1013–1023

    PubMed Central  PubMed  Google Scholar 

  76. MacAulay N, Zeuthen T (2012) Glial K+ clearance and cell swelling: key roles for cotransporters and pumps. Neurochem Res 37:2299–2309

    CAS  PubMed  Google Scholar 

  77. Olsen ML, Sontheimer H (2008) Functional implications for Kir4.1 channels in glial biology: from K+ buffering to cell differentiation. J Neurochem 107:589–601

    PubMed Central  CAS  PubMed  Google Scholar 

  78. Bay V, Butt AM (2012) Relationship between glial potassium regulation and axon excitability: a role for glial Kir4.1 channels. Glia 60:651–660

    PubMed  Google Scholar 

  79. Xu J, Song D, Xue Z, Gu L, Hertz L, Peng L (2013) Requirement of glycogenolysis for uptake of increased extracellular K+ in astrocytes: potential implications for K+ homeostasis and glycogen usage in brain. Neurochem Res 38:472–485

    CAS  PubMed  Google Scholar 

  80. Zanotti S, Charles A (1997) Extracellular calcium sensing by glial cells: low extracellular calcium induces intracellular calcium release and intercellular signaling. J Neurochem 69:594–602

    CAS  PubMed  Google Scholar 

  81. Deitmer JW, Rose CR (2010) Ion changes and signalling in perisynaptic glia. Brain Res Rev 63:113–129

    CAS  PubMed  Google Scholar 

  82. Song D, Man Y, Li B, Xu J, Hertz L, Peng L (2013) Comparison between drug-induced and K+-induced changes in molar acid extrusion fluxes (JH+) and in energy consumption rates in astrocytes. Neurochem Res 38:2364–2374

    CAS  PubMed  Google Scholar 

  83. Amiry-Moghaddam M, Ottersen OP (2003) The molecular basis of water transport in the brain. Nat Rev Neurosci 4:991–1001

    CAS  PubMed  Google Scholar 

  84. Haj-Yasein NN, Jensen V, Ostby I, Omholt SW, Voipio J, Kaila K, Ottersen OP, Hvalby O, Nagelhus EA (2012) Aquaporin-4 regulates extracellular space volume dynamics during high-frequency synaptic stimulation: a gene deletion study in mouse hippocampus. Glia 60:867–874

    PubMed  Google Scholar 

  85. Hamann S, Herrera-Perez JJ, Zeuthen T, Alvarez-Leefmans FJ (2010) Cotransport of water by the Na+–K+–2Cl cotransporter NKCC1 in mammalian epithelial cells. J Physiol 588:4089–4101

    PubMed Central  CAS  PubMed  Google Scholar 

  86. Boison D, Chen JF, Fredholm BB (2010) Adenosine signaling and function in glial cells. Cell Death Differ 17:1071–1082

    PubMed Central  CAS  PubMed  Google Scholar 

  87. Li B, Gu L, Hertz L, Peng L (2013) Expression of nucleoside transporter in freshly isolated neurons and astrocytes from mouse brain. Neurochem Res 38:2351–2358

    CAS  PubMed  Google Scholar 

  88. Pellerin L, Magistretti PJ (2012) Sweet sixteen for ANLS. J Cereb Blood Flow Metab 32:1152–1166

    PubMed Central  CAS  PubMed  Google Scholar 

  89. Mangia S, DiNuzzo M, Giove F, Carruthers A, Simpson IA, Vannucci SJ (2011) Response to ‘comment on recent modeling studies of astrocyte–neuron metabolic interactions’: much ado about nothing. J Cereb Blood Flow Metab 31:1346–1353

    PubMed Central  CAS  PubMed  Google Scholar 

  90. Patel AB, Lai JC, Chowdhury GM, Hyder F, Rothman DL, Shulman RG, Behar KL (2014) Direct evidence for activity-dependent glucose phosphorylation in neurons with implications for the astrocyte-to-neuron lactate shuttle. Proc Natl Acad Sci USA 111:5385–5390

    PubMed Central  CAS  PubMed  Google Scholar 

  91. Nagelhus EA, Ottersen OP (2013) Physiological roles of aquaporin-4 in brain. Physiol Rev 93:1543–1562

    PubMed Central  CAS  PubMed  Google Scholar 

  92. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Trans Med 4:147ra111

    Google Scholar 

  93. Mathiisen TM, Lehre KP, Danbolt NC, Ottersen OP (2010) The perivascular astroglial sheath provides a complete covering of the brain microvessels: an electron microscopic 3D reconstruction. Glia 58:1094–1103

    PubMed  Google Scholar 

  94. Iliff JJ, Lee H, Yu M, Feng T, Logan J, Nedergaard M, Benveniste H (2013) Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Invest 123:1299–1309

    PubMed Central  CAS  PubMed  Google Scholar 

  95. Iliff JJ, Nedergaard M (2013) Is there a cerebral lymphatic system? Stroke 44:S93–S95

    PubMed Central  PubMed  Google Scholar 

  96. Nedergaard M (2013) Neuroscience. Garbage truck of the brain. Science 340:1529–1530

    PubMed Central  CAS  PubMed  Google Scholar 

  97. Iliff JJ, Wang M, Zeppenfeld DM, Venkataraman A, Plog BA, Liao Y, Deane R, Nedergaard M (2013) Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J Neurosci 33:18190–18199

    PubMed Central  CAS  PubMed  Google Scholar 

  98. Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O’Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M (2013) Sleep drives metabolite clearance from the adult brain. Science 342:373–377

    CAS  PubMed  Google Scholar 

  99. Rangroo Thrane V, Thrane AS, Plog BA, Thiyagarajan M, Iliff JJ, Deane R, Nagelhus EA, Nedergaard M (2013) Paravascular microcirculation facilitates rapid lipid transport and astrocyte signaling in the brain. Sci Rep 3:2582

    PubMed  Google Scholar 

  100. Coulter DA, Eid T (2012) Astrocytic regulation of glutamate homeostasis in epilepsy. Glia 60:1215–1226

    PubMed Central  PubMed  Google Scholar 

  101. Giaume C, Kirchhoff F, Matute C, Reichenbach A, Verkhratsky A (2007) Glia: the fulcrum of brain diseases. Cell Death Differ 14:1324–1335

    CAS  PubMed  Google Scholar 

  102. Rajkowska G, Stockmeier CA (2013) Astrocyte pathology in major depressive disorder: insights from human postmortem brain tissue. Curr Drug Targets 14:1225–1236

    PubMed Central  CAS  PubMed  Google Scholar 

  103. Verkhratsky A, Olabarria M, Noristani HN, Yeh CY, Rodriguez JJ (2010) Astrocytes in Alzheimer’s disease. Neurotherapeutics 7:399–412

    CAS  PubMed  Google Scholar 

  104. Verkhratsky A, Rodriguez JJ, Parpura V (2013) Astroglia in neurological diseases. Future Neurol 8:149–158

    PubMed Central  CAS  PubMed  Google Scholar 

  105. Verkhratsky A, Sofroniew MV, Messing A, deLanerolle NC, Rempe D, Rodriguez JJ, Nedergaard M (2012) Neurological diseases as primary gliopathies: a reassessment of neurocentrism. ASN Neuro 4:00082

  106. Burda JE, Sofroniew MV (2014) Reactive gliosis and the multicellular response to CNS damage and disease. Neuron 81:229–248

    PubMed Central  CAS  PubMed  Google Scholar 

  107. Pekny M, Nilsson M (2005) Astrocyte activation and reactive gliosis. Glia 50:427–434

    PubMed  Google Scholar 

  108. Pekny M, Wilhelmsson U, Pekna M (2014) The dual role of astrocyte activation and reactive gliosis. Neurosci Lett 565C:30–38

    Google Scholar 

  109. Sofroniew MV (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 32:638–647

    PubMed Central  CAS  PubMed  Google Scholar 

  110. Hazell AS (2009) Astrocytes are a major target in thiamine deficiency and Wernicke’s encephalopathy. Neurochem Int 55:129–135

    CAS  PubMed  Google Scholar 

  111. Hazell AS, Sheedy D, Oanea R, Aghourian M, Sun S, Jung JY, Wang D, Wang C (2009) Loss of astrocytic glutamate transporters in Wernicke encephalopathy. Glia 58:148–156

    Google Scholar 

  112. Heneka MT, Rodriguez JJ, Verkhratsky A (2010) Neuroglia in neurodegeneration. Brain Res Rev 63:189–211

    CAS  PubMed  Google Scholar 

  113. Rossi D, Brambilla L, Valori CF, Roncoroni C, Crugnola A, Yokota T, Bredesen DE, Volterra A (2008) Focal degeneration of astrocytes in amyotrophic lateral sclerosis. Cell Death Differ 15:1691–1700

    CAS  PubMed  Google Scholar 

  114. De Keyser J, Mostert JP, Koch MW (2008) Dysfunctional astrocytes as key players in the pathogenesis of central nervous system disorders. J Neurol Sci 267:3–16

    PubMed  Google Scholar 

  115. Butterworth RF (2010) Altered glial–neuronal crosstalk: cornerstone in the pathogenesis of hepatic encephalopathy. Neurochem Int 57:383–388

    CAS  PubMed  Google Scholar 

  116. Rangroo Thrane V, Thrane AS, Wang F, Cotrina ML, Smith NA, Chen M, Xu Q, Kang N, Fujita T, Nagelhus EA, Nedergaard M (2013) Ammonia triggers neuronal disinhibition and seizures by impairing astrocyte potassium buffering. Nat Med 19:1643–1648

    PubMed  Google Scholar 

  117. Rose CF, Verkhratsky A, Parpura V (2013) Astrocyte glutamine synthetase: pivotal in health and disease. Biochem Soc Trans 41:1518–1524

    CAS  PubMed  Google Scholar 

  118. Hertz L, Peng L, Song D (2014) Ammonia, like K+, stimulates the Na+, K+, 2 Cl cotransporter NKCC1 and the Na+, K+-ATPase and interacts with endogenous ouabain in astrocytes. Neurochem Res. doi:10.1007/s11064-014-1352-9

  119. Rodriguez JJ, Verkhratsky A (2011) Neuroglial roots of neurodegenerative diseases? Mol Neurobiol 43:87–96

    CAS  PubMed  Google Scholar 

  120. Kulijewicz-Nawrot M, Verkhratsky A, Chvatal A, Sykova E, Rodriguez JJ (2012) Astrocytic cytoskeletal atrophy in the medial prefrontal cortex of a triple transgenic mouse model of Alzheimer’s disease. J Anat 221:252–262

    PubMed Central  PubMed  Google Scholar 

  121. Yeh CY, Vadhwana B, Verkhratsky A, Rodriguez JJ (2011) Early astrocytic atrophy in the entorhinal cortex of a triple transgenic animal model of Alzheimer’s disease. ASN Neuro 3:271–279

    CAS  PubMed  Google Scholar 

  122. Gomirato G, Hyden H (1963) A biochemical glia error in the Parkinson disease. Brain 86:773–780

    CAS  PubMed  Google Scholar 

  123. Duran J, Saez I, Gruart A, Guinovart JJ, Delgado-Garcia JM (2013) Impairment in long-term memory formation and learning-dependent synaptic plasticity in mice lacking glycogen synthase in the brain. J Cereb Blood Flow Metab 33:550–556

    PubMed Central  CAS  PubMed  Google Scholar 

  124. Gibbs ME, Hutchinson D, Hertz L (2008) Astrocytic involvement in learning and memory consolidation. Neurosci Biobehav Rev 32:927–944

    PubMed  Google Scholar 

  125. Verkhratsky A, Rodriguez JJ, Steardo L (2013) Astrogliopathology: A central element of neuropsychiatric diseases? Neuroscientist. doi:10.1177/1073858413510208

  126. Kondziella D, Brenner E, Eyjolfsson EM, Sonnewald U (2007) How do glial–neuronal interactions fit into current neurotransmitter hypotheses of schizophrenia? Neurochem Int 50:291–301

    CAS  PubMed  Google Scholar 

  127. Steiner J, Bogerts B, Sarnyai Z, Walter M, Gos T, Bernstein HG, Myint AM (2012) Bridging the gap between the immune and glutamate hypotheses of schizophrenia and major depression: potential role of glial NMDA receptor modulators and impaired blood–brain barrier integrity. Biol Psychiatry 13:482–492

    Google Scholar 

  128. Guidetti P, Hoffman GE, Melendez-Ferro M, Albuquerque EX, Schwarcz R (2007) Astrocytic localization of kynurenine aminotransferase II in the rat brain visualized by immunocytochemistry. Glia 55:78–92

    PubMed  Google Scholar 

  129. Alexander KS, Wu HQ, Schwarcz R, Bruno JP (2012) Acute elevations of brain kynurenic acid impair cognitive flexibility: normalization by the a7 positive modulator galantamine. Psychopharmacol 220:627–637

    CAS  Google Scholar 

  130. Schwarcz R, Hunter CA (2007) Toxoplasma gondii and schizophrenia: linkage through astrocyte-derived kynurenic acid? Schizophr Bull 33:652–653

    PubMed Central  PubMed  Google Scholar 

  131. Zeidan-Chulia F, Salmina AB, Malinovskaya NA, Noda M, Verkhratsky A, Moreira JC (2014) The glial perspective of autism spectrum disorders. Neurosci Biobehav Rev 38:160–172

    PubMed  Google Scholar 

  132. Tierney E, Bukelis I, Thompson RE, Ahmed K, Aneja A, Kratz L, Kelley RI (2006) Abnormalities of cholesterol metabolism in autism spectrum disorders. Am J Med Gen 141B:666–668

    Google Scholar 

  133. Dringen R, Hirrlinger J (2003) Glutathione pathways in the brain. Biol Chem 384:505–516

    CAS  PubMed  Google Scholar 

  134. Oberheim NA, Tian GF, Han X, Peng W, Takano T, Ransom B, Nedergaard M (2008) Loss of astrocytic domain organization in the epileptic brain. J Neurosci 28:3264–3276

    CAS  PubMed  Google Scholar 

  135. Carmignoto G, Haydon PG (2012) Astrocyte calcium signaling and epilepsy. Glia 60:1227–1233

    PubMed  Google Scholar 

  136. Seifert G, Steinhauser C (2011) Neuron-astrocyte signaling and epilepsy. Exp Neurol 244:4–10

    PubMed  Google Scholar 

  137. Eid T, Lee TS, Wang Y, Perez E, Drummond J, Lauritzen F, Bergersen LH, Meador-Woodruff JH, Spencer DD, de Lanerolle NC, McCullumsmith RE (2013) Gene expression of glutamate metabolizing enzymes in the hippocampal formation in human temporal lobe epilepsy. Epilepsia 54:228–238

    PubMed Central  CAS  PubMed  Google Scholar 

  138. Kielar C, Maddox L, Bible E, Pontikis CC, Macauley SL, Griffey MA, Wong M, Sands MS, Cooper JD (2007) Successive neuron loss in the thalamus and cortex in a mouse model of infantile neuronal ceroid lipofuscinosis. Neurobiol Dis 25:150–162

    PubMed Central  CAS  PubMed  Google Scholar 

  139. Macauley SL, Pekny M, Sands MS (2011) The role of attenuated astrocyte activation in infantile neuronal ceroid lipofuscinosis. J Neurosci 31:15575–15585

    PubMed Central  CAS  PubMed  Google Scholar 

  140. Olabarria M, Noristani HN, Verkhratsky A, Rodriguez JJ (2010) Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer’s disease. Glia 58:831–838

    PubMed  Google Scholar 

  141. Valori CF, Brambilla L, Martorana F, Rossi D (2014) The multifaceted role of glial cells in amyotrophic lateral sclerosis. Cell Mol Life Sci 71:287–297

    CAS  PubMed  Google Scholar 

  142. Potts R, Leech RW (2005) Thalamic dementia: an example of primary astroglial dystrophy of Seitelberger. Clin Neuropathol 24:271–275

    CAS  PubMed  Google Scholar 

  143. Hertz L, Rodrigues TB (2014) Astrocytic-neuronal-astrocytic pathway selection for formation and degradation of glutamate/GABA. Frontiers Endocrinology e-book, Lausanne

    Google Scholar 

Download references

Acknowledgments

MN research is supported by the National Institutes of Health (NIH); AV was supported by the Alzheimer’s Research Trust (UK), by European Commission, by IKERBASQUE and by a research grant of Nizhny Novgorod State University.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Alexei Verkhratsky.

Additional information

Special Issue: In honor of Michael Norenberg.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Verkhratsky, A., Nedergaard, M. & Hertz, L. Why are Astrocytes Important?. Neurochem Res 40, 389–401 (2015). https://doi.org/10.1007/s11064-014-1403-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-014-1403-2

Keywords

Navigation