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General Pathophysiology of Astroglia

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Neuroglia in Neurodegenerative Diseases

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1175))

Abstract

Astroglial cells are involved in most if not in all pathologies of the brain. These cells can change the morpho-functional properties in response to pathology or innate changes of these cells can lead to pathologies. Overall pathological changes in astroglia are complex and diverse and often vary with different disease stages. We classify astrogliopathologies into reactive astrogliosis, astrodegeneration with astroglial atrophy and loss of function, and pathological remodelling of astrocytes. Such changes can occur in neurological, neurodevelopmental, metabolic and psychiatric disorders as well as in infection and toxic insults. Mutation in astrocyte-specific genes leads to specific pathologies, such as Alexander disease, which is a leukodystrophy. We discuss changes in astroglia in the pathological context and identify some molecular entities underlying pathology. These entities within astroglia may repent targets for novel therapeutic intervention in the management of brain pathologies.

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References

  1. Achucarro N (1910) Some pathological findings in the neuroglia and in the ganglion cells of the cortex in senile conditions. Bull Gov Hosp Insane 2:81–90

    Google Scholar 

  2. Alberdi E, Wyssenbach A, Alberdi M, Sanchez-Gomez MV, Cavaliere F, Rodriguez JJ, Verkhratsky A, Matute C (2013) Ca2+-dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid beta-treated astrocytes and in a model of Alzheimer’s disease. Aging Cell 12:292–302

    Article  CAS  PubMed  Google Scholar 

  3. Albrecht J, Zielinska M, Norenberg MD (2010) Glutamine as a mediator of ammonia neurotoxicity: A critical appraisal. Biochem Pharmacol 80:1303–1308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Alexander WS (1949) Progressive fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant. Brain 72:373–381

    Article  CAS  PubMed  Google Scholar 

  5. Allen JW, Shanker G, Aschner M (2001) Methylmercury inhibits the in vitro uptake of the glutathione precursor, cystine, in astrocytes, but not in neurons. Brain Res 894:131–140

    Article  CAS  PubMed  Google Scholar 

  6. Alzheimer A (1910) Beiträge zur Kenntnis der pathologischen Neuroglia und ihrer Beziehungen zu den Abbauvorgängen im Nervengewebe. In: Nissl F, Alzheimer A (eds) Histologische und histopathologische Arbeiten über die Grosshirnrinde mit besonderer Berücksichtigung der pathologischen Anatomie der Geisteskrankheiten. Jena, Gustav Fischer, pp 401–562

    Google Scholar 

  7. Anderson MA, Burda JE, Ren Y, Ao Y, O’Shea TM, Kawaguchi R, Coppola G, Khakh BS, Deming TJ, Sofroniew MV (2016) Astrocyte scar formation aids central nervous system axon regeneration. Nature 532:195–200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Andriezen WL (1893) The neuroglia elements of the brain. Brit Med J 2:227–230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Armstrong V, Reichel CM, Doti JF, Crawford CA, McDougall SA (2004) Repeated amphetamine treatment causes a persistent elevation of glial fibrillary acidic protein in the caudate-putamen. Eur J Pharmacol 488:111–115

    Article  CAS  PubMed  Google Scholar 

  10. Aronica E, Sandau US, Iyer A, Boison D (2013) Glial adenosine kinase–a neuropathological marker of the epileptic brain. Neurochem Int 63:688–695

    Article  CAS  PubMed  Google Scholar 

  11. Aronica E, Zurolo E, Iyer A, de Groot M, Anink J, Carbonell C, van Vliet EA, Baayen JC, Boison D, Gorter JA (2011) Upregulation of adenosine kinase in astrocytes in experimental and human temporal lobe epilepsy. Epilepsia 52:1645–1655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Baker DA, Madayag A, Kristiansen LV, Meador-Woodruff JH, Haroutunian V, Raju I (2008) Contribution of cystine-glutamate antiporters to the psychotomimetic effects of phencyclidine. Neuropsychopharmacology 33:1760–1772

    Article  CAS  PubMed  Google Scholar 

  13. Banasr M, Duman RS (2008) Glial loss in the prefrontal cortex is sufficient to induce depressive-like behaviors. Biol Psychiatry 64:863–870

    Article  PubMed  PubMed Central  Google Scholar 

  14. Barley K, Dracheva S, Byne W (2009) Subcortical oligodendrocyte- and astrocyte-associated gene expression in subjects with schizophrenia, major depression and bipolar disorder. Schizophr Res 112:54–64

    Article  PubMed  Google Scholar 

  15. Basler T, Meier-Hellmann A, Bredle D, Reinhart K (2002) Amino acid imbalance early in septic encephalopathy. Intensive Care Med 28:293–298

    Article  PubMed  Google Scholar 

  16. Bauer D, Gupta D, Harotunian V, Meador-Woodruff JH, McCullumsmith RE (2008) Abnormal expression of glutamate transporter and transporter interacting molecules in prefrontal cortex in elderly patients with schizophrenia. Schizophr Res 104:108–120

    Article  PubMed  PubMed Central  Google Scholar 

  17. Bauer D, Haroutunian V, Meador-Woodruff JH, McCullumsmith RE (2010) Abnormal glycosylation of EAAT1 and EAAT2 in prefrontal cortex of elderly patients with schizophrenia. Schizophr Res 117:92–98

    Article  PubMed  Google Scholar 

  18. Bechtholt-Gompf AJ, Walther HV, Adams MA, Carlezon WA Jr, Ongur D, Cohen BM (2010) Blockade of astrocytic glutamate uptake in rats induces signs of anhedonia and impaired spatial memory. Neuropsychopharmacology 35:2049–2059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bedner P, Dupper A, Huttmann K, Muller J, Herde MK, Dublin P, Deshpande T, Schramm J, Haussler U, Haas CA, Henneberger C, Theis M, Steinhauser C (2015) Astrocyte uncoupling as a cause of human temporal lobe epilepsy. Brain 138:1208–1222

    Article  PubMed  PubMed Central  Google Scholar 

  20. Benedetti B, Matyash V, Kettenmann H (2011) Astrocytes control GABAergic inhibition of neurons in the mouse barrel cortex. J Physiol 589:1159–1172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bernard R, Kerman IA, Thompson RC, Jones EG, Bunney WE, Barchas JD, Schatzberg AF, Myers RM, Akil H, Watson SJ (2011) Altered expression of glutamate signaling, growth factor, and glia genes in the locus coeruleus of patients with major depression. Mol Psychiatry 16:634–646

    Article  CAS  PubMed  Google Scholar 

  22. Bockenhauer D, Feather S, Stanescu HC, Bandulik S, Zdebik AA, Reichold M, Tobin J, Lieberer E, Sterner C, Landoure G, Arora R, Sirimanna T, Thompson D, Cross JH, van’t Hoff W, Al Masri O, Tullus K, Yeung S, Anikster Y, Klootwijk E, Hubank M, Dillon MJ, Heitzmann D, Arcos-Burgos M, Knepper MA, Dobbie A, Gahl WA, Warth R, Sheridan E, Kleta R (2009) Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations. N Engl J Med 360, 1960–1970

    Google Scholar 

  23. Boison D, Aronica E (2015) Comorbidities in neurology: is adenosine the common link? Neuropharmacology 97:18–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bordey A, Sontheimer H (1998) Properties of human glial cells associated with epileptic seizure foci. Epilepsy Res 32:286–303

    Article  CAS  PubMed  Google Scholar 

  25. Bowers MS, Kalivas PW (2003) Forebrain astroglial plasticity is induced following withdrawal from repeated cocaine administration. Eur J Neurosci 17:1273–1278

    Article  PubMed  Google Scholar 

  26. Bowley MP, Drevets WC, Ongur D, Price JL (2002) Low glial numbers in the amygdala in major depressive disorder. Biol Psychiatry 52:404–412

    Article  PubMed  Google Scholar 

  27. Brambilla R, Bracchi-Ricard V, Hu WH, Frydel B, Bramwell A, Karmally S, Green EJ, Bethea JR (2005) Inhibition of astroglial nuclear factor κB reduces inflammation and improves functional recovery after spinal cord injury. J Exp Med 202:145–156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Braun K, Antemano R, Helmeke C, Buchner M, Poeggel G (2009) Juvenile separation stress induces rapid region- and layer-specific changes in S100ss- and glial fibrillary acidic protein-immunoreactivity in astrocytes of the rodent medial prefrontal cortex. Neuroscience 160:629–638

    Article  CAS  PubMed  Google Scholar 

  29. Breslin K, Wade JJ, Wong-Lin K, Harkin J, Flanagan B, Van Zalinge H, Hall S, Walker M, Verkhratsky A, McDaid L (2018) Potassium and sodium microdomains in thin astroglial processes: A computational model study. PLoS Comput Biol 14:e1006151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bridges RJ, Natale NR, Patel SA (2012) System xc- cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS. Br J Pharmacol 165:20–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Brusilow SW, Koehler RC, Traystman RJ, Cooper AJ (2010) Astrocyte glutamine synthetase: importance in hyperammonemic syndromes and potential target for therapy. Neurotherapeutics 7:452–470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Burda JE, Bernstein AM, Sofroniew MV (2016) Astrocyte roles in traumatic brain injury. Exp Neurol 275(Pt 3):305–315

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Burnstock G, Fredholm BB, Verkhratsky A (2011) Adenosine and ATP receptors in the brain. Curr Top Med Chem 11:973–1011

    Article  CAS  PubMed  Google Scholar 

  35. Butterworth RF (2011) Hepatic encephalopathy: a central neuroinflammatory disorder? Hepatology 53:1372–1376

    Article  PubMed  Google Scholar 

  36. Büttner A, Weis S (2006) Neuropathological alterations in drug abusers. The involvement of neurons, glial and vascular systems. Forensic Sci Med Pathol 2:115–126

    Article  PubMed  PubMed Central  Google Scholar 

  37. Campos de Carvalho AC, Roy C, Hertzberg EL, Tanowitz HB, Kessler JA, Weiss LM, Wittner M, Dermietzel R, Gao Y, Spray DC (1998) Gap junction disappearance in astrocytes and leptomeningeal cells as a consequence of protozoan infection. Brain Res 790:304–314

    Article  CAS  PubMed  Google Scholar 

  38. Candelario-Jalil E, Taheri S, Yang Y, Sood R, Grossetete M, Estrada EY, Fiebich BL, Rosenberg GA (2007) Cyclooxygenase inhibition limits blood-brain barrier disruption following intracerebral injection of tumor necrosis factor-alpha in the rat. J Pharmacol Exp Ther 323:488–498

    Article  CAS  PubMed  Google Scholar 

  39. Capuani C, Melone M, Tottene A, Bragina L, Crivellaro G, Santello M, Casari G, Conti F, Pietrobon D (2016) Defective glutamate and K+ clearance by cortical astrocytes in familial hemiplegic migraine type 2. EMBO Mol Med 8:967–986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Carpentier PA, Duncan DS, Miller SD (2008) Glial toll-like receptor signaling in central nervous system infection and autoimmunity. Brain Behav Immun 22:140–147

    Article  CAS  PubMed  Google Scholar 

  41. Cekanaviciute E, Buckwalter MS (2016) Astrocytes: integrative regulators of neuroinflammation in stroke and other neurological diseases. Neurotherapeutics 13:685–701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Cellot G, Cherubini E (2014) GABAergic signaling as therapeutic target for autism spectrum disorders. Front Pediatr 2:70

    Article  PubMed  PubMed Central  Google Scholar 

  43. Chauhan VS, Sterka DG Jr, Furr SR, Young AB, Marriott I (2009) NOD2 plays an important role in the inflammatory responses of microglia and astrocytes to bacterial CNS pathogens. Glia 57:414–423

    Article  PubMed  PubMed Central  Google Scholar 

  44. Chen C, Jiang P, Xue H, Peterson SE, Tran HT, McCann AE, Parast MM, Li S, Pleasure DE, Laurent LC, Loring JF, Liu Y, Deng W (2014) Role of astroglia in Down’s syndrome revealed by patient-derived human-induced pluripotent stem cells. Nat Commun 5:4430

    Article  CAS  PubMed  Google Scholar 

  45. Chepkova AN, Sergeeva OA, Gorg B, Haas HL, Klocker N, Haussinger D (2017) Impaired novelty acquisition and synaptic plasticity in congenital hyperammonemia caused by hepatic glutamine synthetase deficiency. Sci Rep 7:40190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Churchill MJ, Wesselingh SL, Cowley D, Pardo CA, McArthur JC, Brew BJ, Gorry PR (2009) Extensive astrocyte infection is prominent in human immunodeficiency virus-associated dementia. Ann Neurol 66:253–258

    Article  PubMed  Google Scholar 

  47. Combes V, Guillemin GJ, Chan-Ling T, Hunt NH, Grau GE (2012) The crossroads of neuroinflammation in infectious diseases: endothelial cells and astrocytes. Trends Parasitol 28:311–319

    Article  CAS  PubMed  Google Scholar 

  48. Costello JM (1977) A new syndrome: mental subnormality and nasal papillomata. Aust Paediatr J 13:114–118

    CAS  PubMed  Google Scholar 

  49. Cotter D, Mackay D, Chana G, Beasley C, Landau S, Everall IP (2002) Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder. Cereb Cortex 12:386–394

    Article  PubMed  Google Scholar 

  50. Cotter D, Mackay D, Landau S, Kerwin R, Everall I (2001) Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. Arch Gen Psychiatry 58:545–553

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  52. Cullen KM, Halliday GM (1994) Chronic alcoholics have substantial glial pathology in the forebrain and diencephalon. Alcohol Alcohol Suppl 2:253–257

    CAS  PubMed  Google Scholar 

  53. Czeh B, Di Benedetto B (2013) Antidepressants act directly on astrocytes: evidences and functional consequences. Eur Neuropsychopharmacol 23:171–185

    Article  CAS  PubMed  Google Scholar 

  54. Czeh B, Nagy SA (2018) Clinical findings documenting cellular and molecular abnormalities of glia in depressive disorders. Front Mol Neurosci 11:56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Czeh B, Simon M, Schmelting B, Hiemke C, Fuchs E (2006) Astroglial plasticity in the hippocampus is affected by chronic psychosocial stress and concomitant fluoxetine treatment. Neuropsychopharmacology 31:1616–1626

    Article  CAS  PubMed  Google Scholar 

  56. Dantzer R, Kelley KW (2007) Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun 21:153–160

    Article  CAS  PubMed  Google Scholar 

  57. 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

    Article  CAS  PubMed  Google Scholar 

  58. Demarque M, Villeneuve N, Manent JB, Becq H, Represa A, Ben-Ari Y, Aniksztejn L (2004) Glutamate transporters prevent the generation of seizures in the developing rat neocortex. J Neurosci 24:3289–3294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Djukic B, Casper KB, Philpot BD, Chin LS, McCarthy KD (2007) Conditional knock-out of Kir4.1 leads to glial membrane depolarization, inhibition of potassium and glutamate uptake, and enhanced short-term synaptic potentiation. J Neurosci 27:11354–11365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Dong L, Li B, Verkhratsky A, Peng L (2015) Cell type-specific in vivo expression of genes encoding signalling molecules in the brain in response to chronic mild stress and chronic treatment with fluoxetine. Psychopharmacology (Berl)

    Google Scholar 

  61. Dringen R, Gutterer JM, Hirrlinger J (2000) Glutathione metabolism in brain metabolic interaction between astrocytes and neurons in the defense against reactive oxygen species. Eur J Biochem 267:4912–4916

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  63. Dvoriantchikova G, Barakat D, Brambilla R, Agudelo C, Hernandez E, Bethea JR, Shestopalov VI, Ivanov D (2009) Inactivation of astroglial NF-kappa B promotes survival of retinal neurons following ischemic injury. Eur J Neurosci 30:175–185

    Article  PubMed  PubMed Central  Google Scholar 

  64. Eid T, Tu N, Lee TS, Lai JC (2013) Regulation of astrocyte glutamine synthetase in epilepsy. Neurochem Int 63:670–681

    Article  CAS  PubMed  Google Scholar 

  65. El-Hage N, Podhaizer EM, Sturgill J, Hauser KF (2011) Toll-like receptor expression and activation in astroglia: differential regulation by HIV-1 Tat, gp120, and morphine. Immunol Invest 40:498–522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Esen N, Shuffield D, Syed MM, Kielian T (2007) Modulation of connexin expression and gap junction communication in astrocytes by the gram-positive bacterium S. aureus. Glia 55:104–117

    Article  PubMed  PubMed Central  Google Scholar 

  67. Esen N, Tanga FY, DeLeo JA, Kielian T (2004) Toll-like receptor 2 (TLR2) mediates astrocyte activation in response to the Gram-positive bacterium Staphylococcus aureus. J Neurochem 88:746–758

    Article  CAS  PubMed  Google Scholar 

  68. Eugenin EA, Berman JW (2007) Gap junctions mediate human immunodeficiency virus-bystander killing in astrocytes. J Neurosci 27:12844–12850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Falkai P, Bogerts B (1986) Cell loss in the hippocampus of schizophrenics. Eur Arch Psychiatry Neurol Sci 236:154–161

    Article  CAS  PubMed  Google Scholar 

  70. Farina C, Aloisi F, Meinl E (2007) Astrocytes are active players in cerebral innate immunity. Trends Immunol 28:138–145

    Article  CAS  PubMed  Google Scholar 

  71. Fatemi SH, Folsom TD, Reutiman TJ, Lee S (2008) Expression of astrocytic markers aquaporin 4 and connexin 43 is altered in brains of subjects with autism. Synapse 62:501–507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Fattore L, Puddu MC, Picciau S, Cappai A, Fratta W, Serra GP, Spiga S (2002) Astroglial in vivo response to cocaine in mouse dentate gyrus: a quantitative and qualitative analysis by confocal microscopy. Neuroscience 110:1–6

    Article  CAS  PubMed  Google Scholar 

  73. Felipo V (2013) Hepatic encephalopathy: effects of liver failure on brain function. Nat Rev Neurosci 14:851–858

    Article  CAS  PubMed  Google Scholar 

  74. Ferrer I (2018) Astrogliopathy in tauopathies. Neuroglia 1:126–150

    Article  Google Scholar 

  75. Franke H (1995) Influence of chronic alcohol treatment on the GFAP-immunoreactivity in astrocytes of the hippocampus in rats. Acta Histochem 97:263–271

    Article  CAS  PubMed  Google Scholar 

  76. Friend DM, Keefe KA (2013) Glial reactivity in resistance to methamphetamine-induced neurotoxicity. J Neurochem 125:566–574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Frommann C (1878) Untersuchungen über die Gewebsveränderungen bei der Multiplen Sklerose des Gehirns und Rückenmarks. Verlag von Gustav Fischer, Jena

    Google Scholar 

  78. Garcia AD, Petrova R, Eng L, Joyner AL (2010) Sonic hedgehog regulates discrete populations of astrocytes in the adult mouse forebrain. J Neurosci 30:13597–13608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  80. Giovedi S, Corradi A, Fassio A, Benfenati F (2014) Involvement of synaptic genes in the pathogenesis of autism spectrum disorders: the case of synapsins. Front Pediatr 2:94

    PubMed  PubMed Central  Google Scholar 

  81. Gleichman AJ, Carmichael ST (2014) Astrocytic therapies for neuronal repair in stroke. Neurosci Lett 565:47–52

    Article  CAS  PubMed  Google Scholar 

  82. Gorg B, Morwinsky A, Keitel V, Qvartskhava N, Schror K, Haussinger D (2010) Ammonia triggers exocytotic release of L-glutamate from cultured rat astrocytes. Glia 58:691–705

    PubMed  Google Scholar 

  83. Gray LR, Turville SG, Hitchen TL, Cheng WJ, Ellett AM, Salimi H, Roche MJ, Wesselingh SL, Gorry PR, Churchill MJ (2014) HIV-1 entry and trans-infection of astrocytes involves CD81 vesicles. PLoS ONE 9:e90620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Guilarte TR, Nihei MK, McGlothan JL, Howard AS (2003) Methamphetamine-induced deficits of brain monoaminergic neuronal markers: distal axotomy or neuronal plasticity. Neuroscience 122:499–513

    Article  CAS  PubMed  Google Scholar 

  85. Gunnarson E, Axehult G, Baturina G, Zelenin S, Zelenina M, Aperia A (2005) Lead induces increased water permeability in astrocytes expressing aquaporin 4. Neuroscience 136:105–114

    Article  CAS  PubMed  Google Scholar 

  86. Haack N, Dublin P, Rose CR (2014) Dysbalance of astrocyte calcium under hyperammonemic conditions. PLoS ONE 9:e105832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Haberle J, Shahbeck N, Ibrahim K, Hoffmann GF, Ben-Omran T (2011) Natural course of glutamine synthetase deficiency in a 3 year old patient. Mol Genet Metab 103:89–91

    Article  CAS  PubMed  Google Scholar 

  88. Harvey BK, Airavaara M, Hinzman J, Wires EM, Chiocco MJ, Howard DB, Shen H, Gerhardt G, Hoffer BJ, Wang Y (2011) Targeted over-expression of glutamate transporter 1 (GLT-1) reduces ischemic brain injury in a rat model of stroke. PLoS ONE 6:e22135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Heming N, Mazeraud A, Verdonk F, Bozza FA, Chretien F, Sharshar T (2017) Neuroanatomy of sepsis-associated encephalopathy. Crit Care 21:65

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  91. Herman M, Ciancanelli M, Ou YH, Lorenzo L, Klaudel-Dreszler M, Pauwels E, Sancho-Shimizu V, Perez de Diego R, Abhyankar A, Israelsson E, Guo Y, Cardon A, Rozenberg F, Lebon P, Tardieu M, Heropolitanska-Pliszka E, Chaussabel D, White MA, Abel L, Zhang SY, Casanova JL (2012) Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood. J Exp Med 209:1567–1582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Herrmann JE, Imura T, Song B, Qi J, Ao Y, Nguyen TK, Korsak RA, Takeda K, Akira S, Sofroniew MV (2008) STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J Neurosci 28:7231–7243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Heuser K, Nagelhus EA, Tauboll E, Indahl U, Berg PR, Lien S, Nakken S, Gjerstad L, Ottersen OP (2010) Variants of the genes encoding AQP4 and Kir4.1 are associated with subgroups of patients with temporal lobe epilepsy. Epilepsy Res 88:55–64

    Article  CAS  PubMed  Google Scholar 

  94. Hinterkeuser S, Schroder W, Hager G, Seifert G, Blumcke I, Elger CE, Schramm J, Steinhauser C (2000) Astrocytes in the hippocampus of patients with temporal lobe epilepsy display changes in potassium conductances. Eur J Neurosci 12:2087–2096

    Article  CAS  PubMed  Google Scholar 

  95. Hol EM, Pekny M (2015) Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nervous system. Curr Opin Cell Biol 32:121–130

    Article  CAS  PubMed  Google Scholar 

  96. Iovino F, Orihuela CJ, Moorlag HE, Molema G, Bijlsma JJ (2013) Interactions between blood-borne Streptococcus pneumoniae and the blood-brain barrier preceding meningitis. PLoS ONE 8:e68408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Jacobs S, Doering LC (2010) Astrocytes prevent abnormal neuronal development in the fragile x mouse. J Neurosci 30:4508–4514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Jacobs S, Nathwani M, Doering LC (2010) Fragile X astrocytes induce developmental delays in dendrite maturation and synaptic protein expression. BMC Neurosci 11:132

    Article  PubMed  PubMed Central  Google Scholar 

  99. Jassam YN, Izzy S, Whalen M, McGavern DB, El Khoury J (2017) Neuroimmunology of traumatic brain injury: time for a paradigm shift. Neuron 95:1246–1265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kadoi Y, Saito S (1996) An alteration in the gamma-aminobutyric acid receptor system in experimentally induced septic shock in rats. Crit Care Med 24:298–305

    Google Scholar 

  101. Kanemaru K, Kubota J, Sekiya H, Hirose K, Okubo Y, Iino M (2013) Calcium-dependent N-cadherin up-regulation mediates reactive astrogliosis and neuroprotection after brain injury. Proc Natl Acad Sci U S A 110:11612–11617

    Article  PubMed  PubMed Central  Google Scholar 

  102. Karlsen AS, Pakkenberg B (2011) Total numbers of neurons and glial cells in cortex and basal ganglia of aged brains with Down syndrome–a stereological study. Cereb Cortex 21:2519–2524

    Article  PubMed  Google Scholar 

  103. Karlsson RM, Tanaka K, Heilig M, Holmes A (2008) Loss of glial glutamate and aspartate transporter (excitatory amino acid transporter 1) causes locomotor hyperactivity and exaggerated responses to psychotomimetics: rescue by haloperidol and metabotropic glutamate 2/3 agonist. Biol Psychiatry 64:810–814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Karlsson RM, Tanaka K, Saksida LM, Bussey TJ, Heilig M, Holmes A (2009) Assessment of glutamate transporter GLAST (EAAT1)-deficient mice for phenotypes relevant to the negative and executive/cognitive symptoms of schizophrenia. Neuropsychopharmacology 34:1578–1589

    Article  CAS  PubMed  Google Scholar 

  105. Kelly T, Kafitz KW, Roderigo C, Rose CR (2009) Ammonium-evoked alterations in intracellular sodium and pH reduce glial glutamate transport activity. Glia 57:921–934

    Article  PubMed  Google Scholar 

  106. Kelly T, Rose CR (2010) Ammonium influx pathways into astrocytes and neurones of hippocampal slices. J Neurochem 115:1123–1136

    Article  CAS  PubMed  Google Scholar 

  107. Kidd SA, Lachiewicz A, Barbouth D, Blitz RK, Delahunty C, McBrien D, Visootsak J, Berry-Kravis E (2014) Fragile X syndrome: a review of associated medical problems. Pediatrics 134:995–1005

    Article  PubMed  Google Scholar 

  108. Kigerl KA, de Rivero Vaccari JP, Dietrich WD, Popovich PG, Keane RW (2014) Pattern recognition receptors and central nervous system repair. Exp Neurol 258:5–16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  110. Klein RS, Hunter CA (2017) Protective and pathological immunity during central nervous system infections. Immunity 46:891–909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Koss WA, Sadowski RN, Sherrill LK, Gulley JM, Juraska JM (2012) Effects of ethanol during adolescence on the number of neurons and glia in the medial prefrontal cortex and basolateral amygdala of adult male and female rats. Brain Res 1466:24–32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Krencik R, Hokanson KC, Narayan AR, Dvornik J, Rooney GE, Rauen KA, Weiss LA, Rowitch DH, Ullian EM (2015) Dysregulation of astrocyte extracellular signaling in Costello syndrome. Sci Transl Med 7:286ra266

    Google Scholar 

  113. Lanciotti A, Brignone MS, Bertini E, Petrucci TC, Aloisi F, Ambrosini E (2013) Astrocytes: emerging stars in leukodystrophy pathogenesis. Transl Neurosci 4

    Google Scholar 

  114. Larsen BR, Assentoft M, Cotrina ML, Hua SZ, Nedergaard M, Kaila K, Voipio J, MacAulay N (2014) Contributions of the Na+/K+-ATPase, NKCC1, and Kir4.1 to hippocampal K+ clearance and volume responses. Glia 62:608–622

    Article  PubMed  PubMed Central  Google Scholar 

  115. Lauritzen M, Dreier JP, Fabricius M, Hartings JA, Graf R, Strong AJ (2011) Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury. J Cereb Blood Flow Metab 31:17–35

    Article  PubMed  Google Scholar 

  116. Li L, Lundkvist A, Andersson D, Wilhelmsson U, Nagai N, Pardo AC, Nodin C, Stahlberg A, Aprico K, Larsson K, Yabe T, Moons L, Fotheringham A, Davies I, Carmeliet P, Schwartz JP, Pekna M, Kubista M, Blomstrand F, Maragakis N, Nilsson M, Pekny M (2008) Protective role of reactive astrocytes in brain ischemia. J Cereb Blood Flow Metab 28:468–481

    Article  CAS  PubMed  Google Scholar 

  117. Li T, Lan JQ, Boison D (2008) Uncoupling of astrogliosis from epileptogenesis in adenosine kinase (ADK) transgenic mice. Neuron Glia Biol 4:91–99

    Article  PubMed  Google Scholar 

  118. Li T, Quan Lan J, Fredholm BB, Simon RP, Boison D (2007) Adenosine dysfunction in astrogliosis: cause for seizure generation? Neuron Glia Biol 3:353–366

    Article  PubMed  PubMed Central  Google Scholar 

  119. Liang C, Du T, Zhou J, Verkhratsky A, Peng L (2014) Ammonium increases Ca2+ signalling and up-regulates expression of TRPC1 gene in astrocytes in primary cultures and in the in vivo brain. Neurochem Res 39:2127–2135

    Article  CAS  PubMed  Google Scholar 

  120. Liddelow SA, Barres BA (2017) Reactive astrocytes: production, function, and therapeutic potential. Immunity 46:957–967

    Article  CAS  PubMed  Google Scholar 

  121. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Munch AE, Chung WS, Peterson TC, Wilton DK, Frouin A, Napier BA, Panicker N, Kumar M, Buckwalter MS, Rowitch DH, Dawson VL, Dawson TM, Stevens B, Barres BA (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481–487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Liu X, Chauhan VS, Young AB, Marriott I (2010) NOD2 mediates inflammatory responses of primary murine glia to Streptococcus pneumoniae. Glia 58:839–847

    PubMed  PubMed Central  Google Scholar 

  123. Liu Z, Song D, Yan E, Verkhratsky A, Peng L (2015) Chronic treatment with anti-bipolar drugs suppresses glutamate release from astroglial cultures. Amino Acids 47:1045–1051

    Article  CAS  PubMed  Google Scholar 

  124. Lothman EW, Somjen GG (1976) Functions of primary afferents and responses of extracellular K+ during spinal epileptiform seizures. Electroencephalogr Clin Neurophysiol 41:253–267

    Article  CAS  PubMed  Google Scholar 

  125. Makar TK, Nedergaard M, Preuss A, Gelbard AS, Perumal AS, Cooper AJ (1994) Vitamin E, ascorbate, glutathione, glutathione disulfide, and enzymes of glutathione metabolism in cultures of chick astrocytes and neurons: evidence that astrocytes play an important role in antioxidative processes in the brain. J Neurochem 62:45–53

    Article  CAS  PubMed  Google Scholar 

  126. Marcaggi P, Coles JA (2001) Ammonium in nervous tissue: transport across cell membranes, fluxes from neurons to glial cells, and role in signalling. Prog Neurobiol 64:157–183

    Article  CAS  PubMed  Google Scholar 

  127. Marin-Valencia I, Roe CR, Pascual JM (2010). Pyruvate carboxylase deficiency: mechanisms, mimics and anaplerosis. Mol Genet Metab 1:9–17

    Google Scholar 

  128. Masino SA, Li T, Theofilas P, Sandau US, Ruskin DN, Fredholm BB, Geiger JD, Aronica E, Boison D (2011) A ketogenic diet suppresses seizures in mice through adenosine A(1) receptors. J Clin Invest 121:2679–2683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Mc AD, Araki S (1958) Minamata disease: an unusual neurological disorder caused by contaminated fish. Lancet 2:629–631

    Google Scholar 

  130. McGinnis WR (2004) Oxidative stress in autism. Altern Ther Health Med 10:22–36; quiz 37, 92

    Google Scholar 

  131. Messing A, Brenner M, Feany MB, Nedergaard M, Goldman JE (2012) Alexander disease. J Neurosci 32:5017–5023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Miguel-Hidalgo J, Shoyama Y, Wanzo V (2009) Infusion of gliotoxins or a gap junction blocker in the prelimbic cortex increases alcohol preference in Wistar rats. J Psychopharmacol 23:550–557

    Article  CAS  PubMed  Google Scholar 

  133. Miguel-Hidalgo JJ (2005) Lower packing density of glial fibrillary acidic protein-immunoreactive astrocytes in the prelimbic cortex of alcohol-naive and alcohol-drinking alcohol-preferring rats as compared with alcohol-nonpreferring and Wistar rats. Alcohol Clin Exp Res 29:766–772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Miguel-Hidalgo JJ (2009) The role of glial cells in drug abuse. Curr Drug Abuse Rev 2:76–82

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Miguel-Hidalgo JJ, Overholser JC, Meltzer HY, Stockmeier CA, Rajkowska G (2006) Reduced glial and neuronal packing density in the orbitofrontal cortex in alcohol dependence and its relationship with suicide and duration of alcohol dependence. Alcohol Clin Exp Res 30:1845–1855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Minami T, Okazaki J, Kawabata A, Kawaki H, Okazaki Y, Tohno Y (1998) Roles of nitric oxide and prostaglandins in the increased permeability of the blood-brain barrier caused by lipopolysaccharide. Environ Toxicol Pharmacol 5:35–41

    Article  CAS  PubMed  Google Scholar 

  137. Minkiewicz J, de Rivero Vaccari JP, Keane RW (2013) Human astrocytes express a novel NLRP2 inflammasome. Glia 61:1113–1121

    Article  PubMed  Google Scholar 

  138. Miyajima H (2003) Aceruloplasminemia, an iron metabolic disorder. Neuropathology 23:345–350

    Article  PubMed  Google Scholar 

  139. Montana V, Verkhratsky A, Parpura V (2014) Pathological role for exocytotic glutamate release from astrocytes in hepatic encephalopathy. Curr Neuropharmacol 12:324–333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Moody WJ, Futamachi KJ, Prince DA (1974) Extracellular potassium activity during epileptogenesis. Exp Neurol 42:248–263

    Article  CAS  PubMed  Google Scholar 

  141. Moussawi K, Riegel A, Nair S, Kalivas PW (2011) Extracellular glutamate: functional compartments operate in different concentration ranges. Front Syst Neurosci 5:94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Nedergaard M. (1996). Spreading depression as a contributor to ischemic brain damage. Adv Neurol 71:75–83; discussion 83–74

    Google Scholar 

  143. Norenberg MD (1987) The role of astrocytes in hepatic encephalopathy. Neurochem Pathol 6:13–33

    Article  CAS  PubMed  Google Scholar 

  144. Obara-Michlewska M, Ruszkiewicz J, Zielinska M, Verkhratsky A, Albrecht J (2014) Astroglial NMDA receptors inhibit expression of K4.1 channels in glutamate-overexposed astrocytes in vitro and in the brain of rats with acute liver failure. Neurochem Int

    Google Scholar 

  145. Oehmichen M, Meissner C, Reiter A, Birkholz M (1996) Neuropathology in non-human immunodeficiency virus-infected drug addicts: hypoxic brain damage after chronic intravenous drug abuse. Acta Neuropathol 91:642–646

    Article  CAS  PubMed  Google Scholar 

  146. Ohnuma T, Tessler S, Arai H, Faull RL, McKenna PJ, Emson PC (2000) Gene expression of metabotropic glutamate receptor 5 and excitatory amino acid transporter 2 in the schizophrenic hippocampus. Brain Res Mol Brain Res 85:24–31

    Article  CAS  PubMed  Google Scholar 

  147. Oide T, Yoshida K, Kaneko K, Ohta M, Arima K (2006) Iron overload and antioxidative role of perivascular astrocytes in aceruloplasminemia. Neuropathol Appl Neurobiol 32:170–176

    Article  CAS  PubMed  Google Scholar 

  148. Okada S, Nakamura M, Katoh H, Miyao T, Shimazaki T, Ishii K, Yamane J, Yoshimura A, Iwamoto Y, Toyama Y, Okano H (2006) Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. Nat Med 12:829–834

    Article  CAS  PubMed  Google Scholar 

  149. Ongur D, Drevets WC, Price JL (1998) Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci U S A 95:13290–13295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Orellana JA, Saez JC, Bennett MV, Berman JW, Morgello S, Eugenin EA (2014) HIV increases the release of dickkopf-1 protein from human astrocytes by a Cx43 hemichannel-dependent mechanism. J Neurochem 128:752–763

    Article  CAS  PubMed  Google Scholar 

  151. Ortinski PI, Dong J, Mungenast A, Yue C, Takano H, Watson DJ, Haydon PG, Coulter DA (2010) Selective induction of astrocytic gliosis generates deficits in neuronal inhibition. Nat Neurosci 13:584–591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. 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 

  153. Patel SC, Suresh S, Kumar U, Hu CY, Cooney A, Blanchette-Mackie EJ, Neufeld EB, Patel RC, Brady RO, Patel YC, Pentchev PG, Ong WY (1999) Localization of Niemann-Pick C1 protein in astrocytes: implications for neuronal degeneration in Niemann-Pick type C disease. Proc Natl Acad Sci U S A 96:1657–1662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Pekny M, Johansson CB, Eliasson C, Stakeberg J, Wallen A, Perlmann T, Lendahl U, Betsholtz C, Berthold CH, Frisen J (1999) Abnormal reaction to central nervous system injury in mice lacking glial fibrillary acidic protein and vimentin. J Cell Biol 145:503–514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Pekny M, Pekna M (2014) Astrocyte reactivity and reactive astrogliosis: costs and benefits. Physiol Rev 94:1077–1098

    Article  PubMed  Google Scholar 

  156. Pekny M, Pekna M, Messing A, Steinhauser C, Lee JM, Parpura V, Hol EM, Sofroniew MV, Verkhratsky A (2016) Astrocytes: a central element in neurological diseases. Acta Neuropathol 131:323–345

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  158. Piva S, McCreadie VA, Latronico N, Name J (2015) Neuroinflammation in sepsis: sepsis associated delirium. Cardiovasc Hematol Disord Drug Targ 1:10–18

    Google Scholar 

  159. Potokar M, Korva M, Jorgacevski J, Avsic-Zupanc T, Zorec R (2014) Tick-borne encephalitis virus infects rat astrocytes but does not affect their viability. PLoS ONE 9:e86219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Prust M, Wang J, Morizono H, Messing A, Brenner M, Gordon E, Hartka T, Sokohl A, Schiffmann R, Gordish-Dressman H, Albin R, Amartino H, Brockman K, Dinopoulos A, Dotti MT, Fain D, Fernandez R, Ferreira J, Fleming J, Gill D, Griebel M, Heilstedt H, Kaplan P, Lewis D, Nakagawa M, Pedersen R, Reddy A, Sawaishi Y, Schneider M, Sherr E, Takiyama Y, Wakabayashi K, Gorospe JR, Vanderver A (2011) GFAP mutations, age at onset, and clinical subtypes in Alexander disease. Neurology 77:1287–1294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Qrunfleh AM, Alazizi A, Sari Y (2013) Ceftriaxone, a beta-lactam antibiotic, attenuates relapse-like ethanol-drinking behavior in alcohol-preferring rats. J Psychopharmacol 27:541–549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Quaak I, Brouns MR, Van de Bor M (2013) The dynamics of autism spectrum disorders: how neurotoxic compounds and neurotransmitters interact. Int J Environ Res Public Health 10:3384–3408

    Article  PubMed  PubMed Central  Google Scholar 

  163. Rajkowska G, Miguel-Hidalgo JJ, Makkos Z, Meltzer H, Overholser J, Stockmeier C (2002) Layer-specific reductions in GFAP-reactive astroglia in the dorsolateral prefrontal cortex in schizophrenia. Schizophr Res 57:127–138

    Article  PubMed  Google Scholar 

  164. Rajkowska G, Miguel-Hidalgo JJ, Wei J, Dilley G, Pittman SD, Meltzer HY, Overholser JC, Roth BL, Stockmeier CA (1999) Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry 45:1085–1098

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. 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

    Article  CAS  PubMed  Google Scholar 

  167. Rao VL, Dogan A, Todd KG, Bowen KK, Kim BT, Rothstein JD, Dempsey RJ (2001) Antisense knockdown of the glial glutamate transporter GLT-1, but not the neuronal glutamate transporter EAAC1, exacerbates transient focal cerebral ischemia-induced neuronal damage in rat brain. J Neurosci 21:1876–1883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Reinert LS, Harder L, Holm CK, Iversen MB, Horan KA, Dagnaes-Hansen F, Ulhoi BP, Holm TH, Mogensen TH, Owens T, Nyengaard JR, Thomsen AR, Paludan SR (2012) TLR3 deficiency renders astrocytes permissive to herpes simplex virus infection and facilitates establishment of CNS infection in mice. J Clin Invest 122:1368–1376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Reissner KJ, Kalivas PW (2010) Using glutamate homeostasis as a target for treating addictive disorders. Behav Pharmacol 21:514–522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Reissner KJ, Kalivas PW (2014) Emerging roles for glial pathology in addiction. In: Parpura V, Verkhratsky A (eds) Pathological potential of neuroglia: possible new targets for medical intervention. Sprinegr, New York, Heidelberg, Dordrecht, London, pp 397–418

    Google Scholar 

  171. Ren J, Song D, Bai Q, Verkhratsky A, Peng L (2015) Fluoxetine induces alkalinization of astroglial cytosol through stimulation of sodium-hydrogen exchanger 1: dissection of intracellular signaling pathways. Front Cell Neurosci 9:61

    PubMed  PubMed Central  Google Scholar 

  172. Rintala J, Jaatinen P, Kiianmaa K, Riikonen J, Kemppainen O, Sarviharju M, Hervonen A (2001) Dose-dependent decrease in glial fibrillary acidic protein-immunoreactivity in rat cerebellum after lifelong ethanol consumption. Alcohol 23:1–8

    Article  CAS  PubMed  Google Scholar 

  173. Rodriguez JJ, Butt AM, Gardenal E, Parpura V, Verkhratsky A (2016) Complex and differential glial responses in Alzheimer’s disease and ageing. Curr Alzheimer Res 13:343–358

    Article  CAS  PubMed  Google Scholar 

  174. Rojas DC (2014) The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment. J Neural Transm 121:891–905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  176. Rosenbaum AI, Maxfield FR (2011) Niemann-Pick type C disease: molecular mechanisms and potential therapeutic approaches. J Neurochem 116:789–795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. 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

    Article  CAS  PubMed  Google Scholar 

  178. Sanacora G, Banasr M (2013) From pathophysiology to novel antidepressant drugs: glial contributions to the pathology and treatment of mood disorders. Biol Psychiatry 73:1172–1179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Sari Y, Sreemantula SN, Lee MR, Choi DS (2013) Ceftriaxone treatment affects the levels of GLT1 and ENT1 as well as ethanol intake in alcohol-preferring rats. J Mol Neurosci 51:779–787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Google Scholar 

  181. Schmitt A, Steyskal C, Bernstein HG, Schneider-Axmann T, Parlapani E, Schaeffer EL, Gattaz WF, Bogerts B, Schmitz C, Falkai P (2009) Stereologic investigation of the posterior part of the hippocampus in schizophrenia. Acta Neuropathol 117:395–407

    Article  PubMed  Google Scholar 

  182. Scholl UI, Choi M, Liu T, Ramaekers VT, Hausler MG, Grimmer J, Tobe SW, Farhi A, Nelson-Williams C, Lifton RP (2009) Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10. Proc Natl Acad Sci U S A 106:5842–5847

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  184. Sequeira A, Mamdani F, Ernst C, Vawter MP, Bunney WE, Lebel V, Rehal S, Klempan T, Gratton A, Benkelfat C, Rouleau GA, Mechawar N, Turecki G (2009) Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression. PLoS ONE 4:e6585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Shan D, Lucas EK, Drummond JB, Haroutunian V, Meador-Woodruff JH, McCullumsmith RE (2013) Abnormal expression of glutamate transporters in temporal lobe areas in elderly patients with schizophrenia. Schizophr Res 144:1–8

    Article  PubMed  PubMed Central  Google Scholar 

  186. Sharshar T, Annane D, de la Grandmaison GL, Brouland JP, Hopkinson NS, Francoise G (2004) The neuropathology of septic shock. Brain Pathol 14:21–33

    Article  PubMed  Google Scholar 

  187. Shulyatnikova T, Verkhratsky A (2019) Astroglia in sepsis associated encephalopathy. Neurochem Res. E-pub ahead of print. https://doi.org/10.1007/s11064-019-02743-2

  188. Skowronska M, Albrecht J (2012) Alterations of blood brain barrier function in hyperammonemia: an overview. Neurotox Res 21:236–244

    Article  CAS  PubMed  Google Scholar 

  189. Sofroniew MV (2005) Reactive astrocytes in neural repair and protection. Neuroscientist 11:400–407

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Sofroniew MV (2014) Astrogliosis. Cold Spring Harb Perspect Biol 7:a020420

    Article  CAS  PubMed  Google Scholar 

  192. Sofroniew MV (2014) Multiple roles for astrocytes as effectors of cytokines and inflammatory mediators. Neuroscientist 20:160–172

    Article  CAS  PubMed  Google Scholar 

  193. Sofroniew MV (2015) Astrocyte barriers to neurotoxic inflammation. Nat Rev Neurosci 16:249–263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Song P, Zhao ZQ (2001) The involvement of glial cells in the development of morphine tolerance. Neurosci Res 39:281–286

    Article  CAS  PubMed  Google Scholar 

  195. Spodenkiewicz M, Diez-Fernandez C, Rufenacht V, Gemperle-Britschgi C, Haberle J (2016) Minireview on glutamine synthetase deficiency, an ultra-rare inborn error of amino acid biosynthesis. Biology (Basel) 5

    Google Scholar 

  196. Steinhauser C, Grunnet M, Carmignoto G (2015) Crucial role of astrocytes in temporal lobe epilepsy. Neuroscience

    Google Scholar 

  197. Stenzel W, Soltek S, Schluter D, Deckert M (2004) The intermediate filament GFAP is important for the control of experimental murine Staphylococcus aureus-induced brain abscess and Toxoplasma encephalitis. J Neuropathol Exp Neurol 63:631–640

    Article  PubMed  Google Scholar 

  198. Struys-Ponsar C, Guillard O, van den Bosch de Aguilar P (2000) Effects of aluminum exposure on glutamate metabolism: a possible explanation for its toxicity. Exp Neurol 163:157–164

    Google Scholar 

  199. Suarez-Fernandez MB, Soldado AB, Sanz-Medel A, Vega JA, Novelli A, Fernandez-Sanchez MT (1999) Aluminum-induced degeneration of astrocytes occurs via apoptosis and results in neuronal death. Brain Res 835:125–136

    Article  CAS  PubMed  Google Scholar 

  200. Suarez I, Bodega G, Ramos JA, Fernandez-Ruiz JJ, Fernandez B (2000) Neuronal and astroglial response to pre- and perinatal exposure to delta-9-tetra- hydrocannabinol in the rat substantia nigra. Dev Neurosci 22:253–263

    Article  CAS  PubMed  Google Scholar 

  201. Sun JD, Liu Y, Yuan YH, Li J, Chen NH (2012) Gap junction dysfunction in the prefrontal cortex induces depressive-like behaviors in rats. Neuropsychopharmacology 37:1305–1320

    Article  CAS  PubMed  Google Scholar 

  202. Tanaka K, Watase K, Manabe T, Yamada K, Watanabe M, Takahashi K, Iwama H, Nishikawa T, Ichihara N, Kikuchi T, Okuyama S, Kawashima N, Hori S, Takimoto M, Wada K (1997) Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 276:1699–1702

    Article  CAS  PubMed  Google Scholar 

  203. Tang D, Kang R, Coyne CB, Zeh HJ, Lotze MT (2012) PAMPs and DAMPs: signal 0 s that spur autophagy and immunity. Immunol Rev 249:158–175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Tang G, Xu Z, Goldman JE (2006) Synergistic effects of the SAPK/JNK and the proteasome pathway on glial fibrillary acidic protein (GFAP) accumulation in Alexander disease. J Biol Chem 281:38634–38643

    Article  CAS  PubMed  Google Scholar 

  205. Tidyman WE, Rauen KA (2009) The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev 19:230–236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Traynelis SF, Dingledine R (1988) Potassium-induced spontaneous electrographic seizures in the rat hippocampal slice. J Neurophysiol 59:259–276

    Article  CAS  PubMed  Google Scholar 

  207. 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

    Article  CAS  PubMed  Google Scholar 

  208. van Gool WA, van de Beek D, Eikelenboom P (2010) Systemic infection and delirium: when cytokines and acetylcholine collide. Lancet 375:773–775

    Article  CAS  PubMed  Google Scholar 

  209. Varatharaj A, Galea I (2017) The blood-brain barrier in systemic inflammation. Brain Behav Immun 60:1–12

    Article  CAS  PubMed  Google Scholar 

  210. Verkhratsky A, Butt AM (2013) Glial physiology and pathophysiology. Wiley-Blackwell, Chichester

    Book  Google Scholar 

  211. Verkhratsky A, Krishtal OA, Burnstock G (2009) Purinoceptors on neuroglia. Mol Neurobiol 39:190–208

    Article  CAS  PubMed  Google Scholar 

  212. Verkhratsky A, Marutle A, Rodriguez-Arellano JJ, Nordberg A (2015) Glial asthenia and functional paralysis: a new perspective on neurodegeneration and Alzheimer’s disease. Neuroscientist 21:552–568

    Article  CAS  PubMed  Google Scholar 

  213. Verkhratsky A, Nedergaard M (2014) Astroglial cradle in the life of the synapse. Philos Trans R Soc Lond B Biol Sci 369:20130595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Verkhratsky A, Nedergaard M (2018) Physiology of astroglia. Physiol Rev 98:239–389

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Verkhratsky A, Parpura V (2016) Astrogliopathology in neurological, neurodevelopmental and psychiatric disorders. Neurobiol Dis 85:254–261

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Verkhratsky A, Rodriguez JJ, Steardo L (2014) Astrogliopathology: a central element of neuropsychiatric diseases? Neuroscientist 20:576–588

    Article  PubMed  Google Scholar 

  219. Verkhratsky A, Steardo L, Parpura V, Montana V (2016) Translational potential of astrocytes in brain disorders. Prog Neurobiol 144:188–205

    Article  CAS  PubMed  Google Scholar 

  220. Verkhratsky A, Zorec R, Parpura V (2017) Stratification of astrocytes in healthy and diseased brain. Brain Pathol 27:629–644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Verkhratsky A, Zorec R, Rodriguez JJ, Parpura V (2017) Neuroglia: functional paralysis and reactivity in Alzheimer’s disease and other neurodegenerative pathologies. Adv Neurobiol 15:427–449

    Article  PubMed  Google Scholar 

  222. Virchow R (1858) Die Cellularpathologie in ihrer Begründung auf physiologische and pathologische Gewebelehre. Zwanzig Vorlesungen gehalten während der Monate Februar, März und April 1858 im pathologischen Institut zu Berlin. August Hirschwald, Berlin

    Google Scholar 

  223. Wang F, Du T, Liang C, Verkhratsky A, Peng L (2015) Ammonium increases Ca2+ signalling and upregulates expression of Cav1.2 gene in astrocytes in primary cultures and in the in vivo brain. Acta Physiol (Oxf) 214:261–274

    Article  CAS  Google Scholar 

  224. Wang Y, Zaveri HP, Lee TS, Eid T (2009) The development of recurrent seizures after continuous intrahippocampal infusion of methionine sulfoximine in rats: a video-intracranial electroencephalographic study. Exp Neurol 220:293–302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Weber M, Scherf N, Kahl T, Braumann UD, Scheibe P, Kuska JP, Bayer R, Buttner A, Franke H (2013) Quantitative analysis of astrogliosis in drug-dependent humans. Brain Res 1500:72–87

    Article  CAS  PubMed  Google Scholar 

  226. Webster MJ, Knable MB, Johnston-Wilson N, Nagata K, Inagaki M, Yolken RH (2001) Immunohistochemical localization of phosphorylated glial fibrillary acidic protein in the prefrontal cortex and hippocampus from patients with schizophrenia, bipolar disorder, and depression. Brain Behav Immun 15:388–400

    Article  CAS  PubMed  Google Scholar 

  227. Weng YC, Kriz J (2007) Differential neuroprotective effects of a minocycline-based drug cocktail in transient and permanent focal cerebral ischemia. Exp Neurol 204:433–442

    Article  CAS  PubMed  Google Scholar 

  228. Wilson EH, Hunter CA (2004) The role of astrocytes in the immunopathogenesis of toxoplasmic encephalitis. Int J Parasitol 34:543–548

    Article  CAS  PubMed  Google Scholar 

  229. Wilson JX, Peters CE, Sitar SM, Daoust P, Gelb AW (2000) Glutamate stimulates ascorbate transport by astrocytes. Brain Res 858:61–66

    Article  CAS  PubMed  Google Scholar 

  230. Windrem MS, Osipovitch M, Liu Z, Bates J, Chandler-Militello D, Zou L, Munir J, Schanz S, McCoy K, Miller RH, Wang S, Nedergaard M, Findling RL, Tesar PJ, Goldman SA (2017) Human iPSC glial mouse chimeras reveal glial contributions to schizophrenia. Cell Stem Cell 21(195–208):e196

    Google Scholar 

  231. Xia M, Abazyan S, Jouroukhin Y, Pletnikov M (2014) Behavioral sequelae of astrocyte dysfunction: focus on animal models of schizophrenia. Schizophr Res

    Google Scholar 

  232. Yin Z, Milatovic D, Aschner JL, Syversen T, Rocha JB, Souza DO, Sidoryk M, Albrecht J, Aschner M (2007) Methylmercury induces oxidative injury, alterations in permeability and glutamine transport in cultured astrocytes. Brain Res 1131:1–10

    Article  CAS  PubMed  Google Scholar 

  233. Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, Giffard RG, Barres BA (2012) Genomic analysis of reactive astrogliosis. J Neurosci 32:6391–6410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. 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

    Article  PubMed  Google Scholar 

  235. Zhang L, Li L, Wang B, Qian DM, Song XM, Hu M (2013) Human cytomegalovirus infection modulates thrombospondins 1 and 2 in primary fetal astrocytes. NeuroReport 24:526–535

    Article  CAS  PubMed  Google Scholar 

  236. Zhang L, Li L, Wang B, Qian DM, Song XX, Hu M (2014) HCMV induces dysregulation of glutamate uptake and transporter expression in human fetal astrocytes. Neurochem Res 39:2407–2418

    Article  CAS  PubMed  Google Scholar 

  237. Zhang M, Strnatka D, Donohue C, Hallows JL, Vincent I, Erickson RP (2008) Astrocyte-only Npc1 reduces neuronal cholesterol and triples life span of Npc1-/- mice. J Neurosci Res 86:2848–2856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Zhang Y, Jin Y, Behr MJ, Feustel PJ, Morrison JP, Kimelberg HK (2005) Behavioral and histological neuroprotection by tamoxifen after reversible focal cerebral ischemia. Exp Neurol 196:41–46

    Article  CAS  PubMed  Google Scholar 

  239. Zhao Y, Rempe DA (2010) Targeting astrocytes for stroke therapy. Neurotherapeutics 7:439–451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Zorec R, Zupanc TA, Verkhratsky A (2019) Astrogliopathology in the infectious insults of the brain. Neurosci Lett 689:56–62

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

VP’s work is supported by a grant from the National Institute of General Medical Sciences of the National Institutes of Health (R01GM123971). VP is an Honorary Professor at University of Rijeka, Croatia.

Author information

Authors and Affiliations

  1. Faculty of Biology, Medicine and Health, The University of Manchester, Oxford Road, Manchester, M13 9PT, UK

    Alexei Verkhratsky

  2. Center for Basic and Translational Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark

    Alexei Verkhratsky

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

    Alexei Verkhratsky

  4. School of Life Science and Technology, ShanghaiTech University, 201210, Shanghai, China

    Margaret S. Ho

  5. Laboratory of Neuroendocrinology-Molecular Cell Physiology, Faculty of Medicine, Institute of Pathophysiology, University of Ljubljana, Ljubljana, Slovenia

    Nina Vardjan & Robert Zorec

  6. Celica BIOMEDICAL, Ljubljana, Slovenia

    Nina Vardjan & Robert Zorec

  7. Department of Neurobiology, The University of Alabama at Birmingham, Birmingham, AL, USA

    Vladimir Parpura

Authors
  1. Alexei Verkhratsky
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  2. Margaret S. Ho
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  3. Nina Vardjan
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  4. Robert Zorec
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  5. Vladimir Parpura
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Corresponding author

Correspondence to Alexei Verkhratsky .

Editor information

Editors and Affiliations

  1. Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK

    Alexei Verkhratsky

  2. School of Life Science and Technology, ShanghaiTech University, Shanghai, China

    Margaret S. Ho

  3. Institute of Pathophysiology, University of Ljubljana, Ljubljana, Slovenia

    Robert Zorec

  4. Department of Neurobiology, The University of Alabama at Birmingham, Birmingham, AL, USA

    Vladimir Parpura

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Verkhratsky, A., Ho, M.S., Vardjan, N., Zorec, R., Parpura, V. (2019). General Pathophysiology of Astroglia. In: Verkhratsky, A., Ho, M., Zorec, R., Parpura, V. (eds) Neuroglia in Neurodegenerative Diseases. Advances in Experimental Medicine and Biology, vol 1175. Springer, Singapore. https://doi.org/10.1007/978-981-13-9913-8_7

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