Acta Neuropathologica

, Volume 131, Issue 3, pp 323–345 | Cite as

Astrocytes: a central element in neurological diseases

  • Milos PeknyEmail author
  • Marcela Pekna
  • Albee Messing
  • Christian Steinhäuser
  • Jin-Moo Lee
  • Vladimir Parpura
  • Elly M. Hol
  • Michael V. Sofroniew
  • Alexei VerkhratskyEmail author


The neurone-centred view of the past disregarded or downplayed the role of astroglia as a primary component in the pathogenesis of neurological diseases. As this concept is changing, so is also the perceived role of astrocytes in the healthy and diseased brain and spinal cord. We have started to unravel the different signalling mechanisms that trigger specific molecular, morphological and functional changes in reactive astrocytes that are critical for repairing tissue and maintaining function in CNS pathologies, such as neurotrauma, stroke, or neurodegenerative diseases. An increasing body of evidence shows that the effects of astrogliosis on the neural tissue and its functions are not uniform or stereotypic, but vary in a context-specific manner from astrogliosis being an adaptive beneficial response under some circumstances to a maladaptive and deleterious process in another context. There is a growing support for the concept of astrocytopathies in which the disruption of normal astrocyte functions, astrodegeneration or dysfunctional/maladaptive astrogliosis are the primary cause or the main factor in neurological dysfunction and disease. This review describes the multiple roles of astrocytes in the healthy CNS, discusses the diversity of astroglial responses in neurological disorders and argues that targeting astrocytes may represent an effective therapeutic strategy for Alexander disease, neurotrauma, stroke, epilepsy and Alzheimer’s disease as well as other neurodegenerative diseases.


Astrocytes Astroglial cells Reactive astrogliosis Reactive gliosis Astrocytopathies Neurotrauma Stroke Epilepsy Alzheimer’s disease Alexander disease Huntington disease Neurological diseases 



The authors thank Roy Pekny for critical comments on the manuscript and acknowledge support from the Swedish Medical Research Council (Project 11548 and 20116), Deutsche Forschungsgemeinschaft (STE 552/3), AFA Research Foundation, ALF Göteborg (Project 11392 and 142821), Sten A. Olsson Foundation for Research and Culture, Söderberg Foundations, Hjärnfonden, Hagströmer’s Foundation Millennium, the Swedish Stroke Foundation, the Swedish Society for Medical Research, the Free Mason Foundation, Amlöv’s Foundation, E. Jacobson’s Donation Fund, NanoNet COST Action, (BM1002), the EU FP 7 Programs EduGlia (237956), NeuroGLIA (202167), EuroEPINOMICS and TargetBraIn (279017). AV was supported, in part, by the Grant (agreement from August 27 2013 No. 02.B.49.21.0003) between The Ministry of Education and Science of the Russian Federation and Lobachevsky State University of Nizhny Novgorod, by the Ministry of education of Russian Federation, unique identity number of the project is RFMEFI57814X0079, and by the grant of the Russian Scientific Foundation No. 14-15-00633. VP’s work is supported by the National Institutes of Health (HD078678). The concept of this review was conceived at the conference and training school Astrocyte Intermediate Filaments (Nanofilaments) and Astrocyte Function in Health and Disease, held at the University of Gothenburg, Sweden, in 2014, supported by NanoNet COST Action (BM1002), and the Swedish Medical Research Council, with the authors of this review as speakers.


  1. 1.
    Aimone JB, Deng W, Gage FH (2011) Resolving new memories: a critical look at the dentate gyrus, adult neurogenesis, and pattern separation. Neuron 70:589–596PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M, Davis KL, Farlow MR, Jin S, Thomas RG, Thal LJ et al (2003) Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA 289:2819–2826PubMedCrossRefGoogle Scholar
  3. 3.
    Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL et al (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21:383–421PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Allaman I, Gavillet M, Belanger M, Laroche T, Viertl D, Lashuel HA, Magistretti PJ (2010) Amyloid-β aggregates cause alterations of astrocytic metabolic phenotype: impact on neuronal viability. J Neurosci 30:3326–3338PubMedCrossRefGoogle Scholar
  5. 5.
    Allen NJ, Bennett ML, Foo LC, Wang GX, Chakraborty C, Smith SJ, Barres BA (2012) Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors. Nature 486:410–414PubMedCentralPubMedCrossRefGoogle Scholar
  6. 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. Gustav Fischer, City, pp 401–562Google Scholar
  7. 7.
    Anderson MA, Ao Y, Sofroniew MV (2014) Heterogeneity of reactive astrocytes. Neurosci Lett 565C:23–29CrossRefGoogle Scholar
  8. 8.
    Angulo MC, Kozlov AS, Charpak S, Audinat E (2004) Glutamate released from glial cells synchronizes neuronal activity in the hippocampus. J Neurosci 24:6920–6927PubMedCrossRefGoogle Scholar
  9. 9.
    Araque A, Carmignoto G, Haydon PG, Oliet SH, Robitaille R, Volterra A (2014) Gliotransmitters travel in time and space. Neuron 81:728–739PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Balasingam V, Tejada-Berges T, Wright E, Bouckova R, Yong VW (1994) Reactive astrogliosis in the neonatal mouse brain and its modulation by cytokines. J Neurosci 14:846–856PubMedGoogle Scholar
  11. 11.
    Bardehle S, Kruger M, Buggenthin F, Schwausch J, Ninkovic J, Clevers H, Snippert HJ, Theis FJ, Meyer-Luehmann M, Bechmann I et al (2013) Live imaging of astrocyte responses to acute injury reveals selective juxtavascular proliferation. Nat Neurosci 16:580–586PubMedCrossRefGoogle Scholar
  12. 12.
    Barkho BZ, Song H, Aimone JB, Smrt RD, Kuwabara T, Nakashima K, Gage FH, Zhao X (2006) Identification of astrocyte-expressed factors that modulate neural stem/progenitor cell differentiation. Stem Cells Devel 15:407–421CrossRefGoogle Scholar
  13. 13.
    Basak JM, Verghese PB, Yoon H, Kim J, Holtzman DM (2012) Low-density lipoprotein receptor represents an apolipoprotein E-independent pathway of Abeta uptake and degradation by astrocytes. J Biol Chem 287:13959–13971PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Beauquis J, Pavia P, Pomilio C, Vinuesa A, Podlutskaya N, Galvan V, Saravia F (2013) Environmental enrichment prevents astroglial pathological changes in the hippocampus of APP transgenic mice, model of Alzheimer’s disease. Exp Neurol 239:28–37PubMedCrossRefGoogle Scholar
  15. 15.
    Bedner P, Dupper A, Huttmann K, Muller J, Herde MK, Dublin P, Deshpande T, Schramm J, Haussler U, Haas CA et al (2015) Astrocyte uncoupling as a cause of human temporal lobe epilepsy. Brain 138:1208–1222PubMedCrossRefGoogle Scholar
  16. 16.
    Bedner P, Steinhauser C (2013) Altered Kir and gap junction channels in temporal lobe epilepsy. Neurochem Int 63:682–687PubMedCrossRefGoogle Scholar
  17. 17.
    Behrens PF, Franz P, Woodman B, Lindenberg KS, Landwehrmeyer GB (2002) Impaired glutamate transport and glutamate-glutamine cycling: downstream effects of the Huntington mutation. Brain 125:1908–1922PubMedCrossRefGoogle Scholar
  18. 18.
    Bell RD, Zlokovic BV (2009) Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer’s disease. Acta Neuropathol 118:103–113PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Benner EJ, Luciano D, Jo R, Abdi K, Paez-Gonzalez P, Sheng H, Warner DS, Liu C, Eroglu C, Kuo CT (2013) Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4. Nature 497:369–373PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Berg A, Zelano J, Stephan A, Thams S, Barres BA, Pekny M, Pekna M, Cullheim S (2012) Reduced removal of synaptic terminals from axotomized spinal motoneurons in the absence of complement C3. Exp Neurol 237:8–17PubMedCrossRefGoogle Scholar
  21. 21.
    Bettens K, Sleegers K, Van Broeckhoven C (2013) Genetic insights in Alzheimer’s disease. Lancet Neurol 12:92–104PubMedCrossRefGoogle Scholar
  22. 22.
    Bhalala OG, Pan L, Sahni V, McGuire TL, Gruner K, Tourtellotte WG, Kessler JA (2012) microRNA-21 regulates astrocytic response following spinal cord injury. J Neurosci 32:17935–17947PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Bialas AR, Stevens B (2013) TGF-beta signaling regulates neuronal C1q expression and developmental synaptic refinement. Nat Neurosci 16:1773–1782PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Bradbury EJ, Carter LM (2011) Manipulating the glial scar: chondroitinase ABC as a therapy for spinal cord injury. Brain Res Bull 84:306–316PubMedCrossRefGoogle Scholar
  25. 25.
    Bradbury EJ, Moon LDF, Popat RJ, King VR, Bennett GS, Patel PN, Fawcett JW, McMahon SB (2002) Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 416:636–640PubMedCrossRefGoogle Scholar
  26. 26.
    Brambilla R, Bracchi-Ricard V, Hu WH, Frydel B, Bramwell A, Karmally S, Green EJ, Bethea JR (2005) Inhibition of astroglial nuclear factor kappaB reduces inflammation and improves functional recovery after spinal cord injury. J Exp Med 202:145–156PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Brambilla R, Persaud T, Hu X, Karmally S, Shestopalov VI, Dvoriantchikova G, Ivanov D, Nathanson L, Barnum SR, Bethea JR (2009) Transgenic inhibition of astroglial NF-kappaB improves functional outcome in experimental autoimmune encephalomyelitis by suppressing chronic central nervous system inflammation. J Immunol 182:2628–2640PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Buffo A, Rite I, Tripathi P, Lepier A, Colak D, Horn AP, Mori T, Gotz M (2008) Origin and progeny of reactive gliosis: a source of multipotent cells in the injured brain. Proc Natl Acad Sci 105:3581–3586PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Buffo A, Rolando C, Ceruti S (2010) Astrocytes in the damaged brain: molecular and cellular insights into their reactive response and healing potential. Biochem Pharmacol 79:77–89PubMedCrossRefGoogle Scholar
  30. 30.
    Burda JE, Sofroniew MV (2014) Reactive gliosis and the multicellular response to CNS damage and disease. Neuron 81:229–248PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Bush TG, Puvanachandra N, Horner CH, Polito A, Ostenfeld T, Svendsen CN, Mucke L, Johnson MH, Sofroniew MV (1999) Leukocyte infiltration, neuronal degeneration and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron 23:297–308Google Scholar
  32. 32.
    Bush TG, Puvanachandra N, Horner CH, Polito A, Ostenfeld T, Svendsen CN, Mucke L, Johnson MH, Sofroniew MV (1999) Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron 23:297–308PubMedCrossRefGoogle Scholar
  33. 33.
    Bushong EA, Martone ME, Jones YZ, Ellisman MH (2002) Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J Neurosci 22:183–192PubMedGoogle Scholar
  34. 34.
    Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS, Xing Y, Lubischer JL, Krieg PA, Krupenko SA et al (2008) A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci 28:264–278PubMedCrossRefGoogle Scholar
  35. 35.
    Chalermpalanupap T, Kinkead B, Hu WT, Kummer MP, Hammerschmidt T, Heneka MT, Weinshenker D, Levey AI (2013) Targeting norepinephrine in mild cognitive impairment and Alzheimer’s disease. Alzheimers Res Ther 5:21PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Chen DF, Schneider GE, Martinou JC, Tonegawa S (1997) Bcl-2 promotes regeneration of severed axons in mammalian CNS. Nature 385:434–439PubMedCrossRefGoogle Scholar
  37. 37.
    Chever O, Djukic B, McCarthy KD, Amzica F (2010) Implication of Kir4.1 channel in excess potassium clearance: an in vivo study on anesthetized glial-conditional Kir4.1 knock-out mice. J Neurosci 30:15769–15777PubMedCrossRefGoogle Scholar
  38. 38.
    Cho KS, Yang L, Lu B, Feng Ma H, Huang X, Pekny M, Chen DF (2005) Re-establishing the regenerative potential of central nervous system axons in postnatal mice. J Cell Sci 118:863–872PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Christopherson KS, Ullian EM, Stokes CC, Mullowney CE, Hell JW, Agah A, Lawler J, Mosher DF, Bornstein P, Barres BA (2005) Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120:421–433PubMedCrossRefGoogle Scholar
  40. 40.
    Chung WS, Clarke LE, Wang GX, Stafford BK, Sher A, Chakraborty C, Joung J, Foo LC, Thompson A, Chen C et al (2013) Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 504:394–400PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Coleman P, Federoff H, Kurlan R (2004) A focus on the synapse for neuroprotection in Alzheimer disease and other dementias. Neurology 63:1155–1162PubMedCrossRefGoogle Scholar
  42. 42.
    Colucci-Guyon E, Portier MM, Dunia I, Paulin D, Pournin S, Babinet C (1994) Mice lacking vimentin develop and reproduce without an obvious phenotype. Cell 79:679–694PubMedCrossRefGoogle Scholar
  43. 43.
    Coras R, Siebzehnrubl FA, Pauli E, Huttner HB, Njunting M, Kobow K, Villmann C, Hahnen E, Neuhuber W, Weigel D et al (2010) Low proliferation and differentiation capacities of adult hippocampal stem cells correlate with memory dysfunction in humans. Brain 133:3359–3372PubMedCrossRefGoogle Scholar
  44. 44.
    Coulter DA, Eid T (2012) Astrocytic regulation of glutamate homeostasis in epilepsy. Glia 60:1215–1226PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Cregg JM, DePaul MA, Filous AR, Lang BT, Tran A, Silver J (2014) Functional regeneration beyond the glial scar. Exp Neurol 253:197–207PubMedCrossRefGoogle Scholar
  46. 46.
    Croisier E, Graeber MB (2006) Glial degeneration and reactive gliosis in alpha-synucleinopathies: the emerging concept of primary gliodegeneration. Acta Neuropathol 112:517–530PubMedCrossRefGoogle Scholar
  47. 47.
    Cuervo AM, Dice JF (2000) When lysosomes get old. Exp Gerontol 35:119–131PubMedCrossRefGoogle Scholar
  48. 48.
    de Pablo Y, Nilsson M, Pekna M, Pekny M (2013) Intermediate filaments are important for astrocyte response to oxidative stress induced by oxygen-glucose deprivation and reperfusion. Histochem Cell Biol 140:81–91PubMedCrossRefGoogle Scholar
  49. 49.
    DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27:457–464PubMedCrossRefGoogle Scholar
  50. 50.
    Deng W, Saxe MD, Gallina IS, Gage FH (2009) Adult-born hippocampal dentate granule cells undergoing maturation modulate learning and memory in the brain. J Neurosci 29:13532–13542PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Dimou L, Gotz M (2014) Glial cells as progenitors and stem cells: new roles in the healthy and diseased brain. Physiol Rev 94:709–737PubMedCrossRefGoogle Scholar
  52. 52.
    Ding F, O’Donnell J, Thrane AS, Zeppenfeld D, Kang H, Xie L, Wang F, Nedergaard M (2013) α1-Adrenergic receptors mediate coordinated Ca2+ signaling of cortical astrocytes in awake, behaving mice. Cell Calcium 54:387–394PubMedCrossRefGoogle Scholar
  53. 53.
    Ding M, Eliasson C, Betsholtz C, Hamberger A, Pekny M (1998) Altered taurine release following hypotonic stress in astrocytes from mice deficient for GFAP and vimentin. Brain Res Mol Brain Res 62:77–81PubMedCrossRefGoogle Scholar
  54. 54.
    Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97:703–716PubMedCrossRefGoogle Scholar
  55. 55.
    Doetsch F, Garcia-Verdugo JM, Alvarez-Buylla A (1997) Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain. J Neurosci 17:5046–5061PubMedGoogle Scholar
  56. 56.
    Drogemuller K, Helmuth U, Brunn A, Sakowicz-Burkiewicz M, Gutmann DH, Mueller W, Deckert M, Schluter D (2008) Astrocyte gp130 expression is critical for the control of Toxoplasma encephalitis. J Immunol 181:2683–2693PubMedCrossRefGoogle Scholar
  57. 57.
    Eroglu C, Allen NJ, Susman MW, O’Rourke NA, Park CY, Ozkan E, Chakraborty C, Mulinyawe SB, Annis DS, Huberman AD et al (2009) Gabapentin receptor α2δ-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell 139:380–392PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Estrada-Sánchez AM, Rebec GV (2012) Corticostriatal dysfunction and glutamate transporter 1 (GLT1) in Huntington’s disease: Interactions between neurons and astrocytes. Basal Ganglia 2:57–66PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Faideau M, Kim J, Cormier K, Gilmore R, Welch M, Auregan G, Dufour N, Guillermier M, Brouillet E, Hantraye P et al (2010) In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington’s disease subjects. Hum Mol Genet 19:3053–3067PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, Sofroniew MV (2004) Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci 24:2143–2155PubMedCrossRefGoogle Scholar
  61. 61.
    Fellin T, Pascual O, Gobbo S, Pozzan T, Haydon PG, Carmignoto G (2004) Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron 43:729–743PubMedCrossRefGoogle Scholar
  62. 62.
    Funato H, Yoshimura M, Yamazaki T, Saido TC, Ito Y, Yokofujita J, Okeda R, Ihara Y (1998) Astrocytes containing amyloid β-protein (Aβ)-positive granules are associated with Aβ40-positive diffuse plaques in the aged human brain. Am J Pathol 152:983–992PubMedCentralPubMedGoogle Scholar
  63. 63.
    Furman JL, Sama DM, Gant JC, Beckett TL, Murphy MP, Bachstetter AD, Van Eldik LJ, Norris CM (2012) Targeting astrocytes ameliorates neurologic changes in a mouse model of Alzheimer’s disease. J Neurosci 32:16129–16140PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Gadea A, Schinelli S, Gallo V (2008) Endothelin-1 regulates astrocyte proliferation and reactive gliosis via a JNK/c-Jun signaling pathway. J Neurosci 28:2394–2408PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Galanopoulou AS, Buckmaster PS, Staley KJ, Moshe SL, Perucca E, Engel J Jr, Loscher W, Noebels JL, Pitkanen A, Stables J et al (2012) Identification of new epilepsy treatments: issues in preclinical methodology. Epilepsia 53:571–582PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Gao K, Wang CR, Jiang F, Wong AY, Su N, Jiang JH, Chai RC, Vatcher G, Teng J, Chen J et al (2013) Traumatic scratch injury in astrocytes triggers calcium influx to activate the JNK/c-Jun/AP-1 pathway and switch on GFAP expression. Glia 61:2063–2077PubMedCrossRefGoogle Scholar
  67. 67.
    Gao Q, Wolfgang MJ, Neschen S, Morino K, Horvath TL, Shulman GI, Fu XY (2004) Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation. Proc Natl Acad Sci 101:4661–4666PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Garcia AD, Doan NB, Imura T, Bush TG, Sofroniew MV (2004) GFAP-expressing progenitors are the principal source of constitutive neurogenesis in adult mouse forebrain. Nat Neurosci 7:1233–1241PubMedCrossRefGoogle Scholar
  69. 69.
    Garcia AD, Petrova R, Eng L, Joyner AL (2010) Sonic hedgehog regulates discrete populations of astrocytes in the adult mouse forebrain. J Neurosci 30:13597–13608PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Giaume C, Koulakoff A, Roux L, Holcman D, Rouach N (2010) Astroglial networks: a step further in neuroglial and gliovascular interactions. Nat Rev Neurosci 11:87–99PubMedCrossRefGoogle Scholar
  71. 71.
    Glass M, Dragunow M (1995) Neurochemical and morphological changes associated with human epilepsy. Brain Res Brain Res Rev 21:29–41PubMedCrossRefGoogle Scholar
  72. 72.
    Goritz C, Dias DO, Tomilin N, Barbacid M, Shupliakov O, Frisen J (2011) A pericyte origin of spinal cord scar tissue. Science 333:238–242PubMedCrossRefGoogle Scholar
  73. 73.
    Gray M (2014) The role of astrocytes in Huntington’s disease. In: Parpura V, Verkhratsky A (eds) Pathological potentual of neuroglia Possible new targets for medical intervention. Springer, City, pp 213–229Google Scholar
  74. 74.
    Grolla AA, Sim JA, Lim D, Rodriguez JJ, Genazzani AA, Verkhratsky A (2013) Amyloid-β and Alzheimer’s disease type pathology differentially affects the calcium signalling toolkit in astrocytes from different brain regions. Cell Death Dis 4:e623PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Gu X, Andre VM, Cepeda C, Li SH, Li XJ, Levine MS, Yang XW (2007) Pathological cell-cell interactions are necessary for striatal pathogenesis in a conditional mouse model of Huntington’s disease. Mol Neurodegener 2:8PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Gu X, Li C, Wei W, Lo V, Gong S, Li SH, Iwasato T, Itohara S, Li XJ, Mody I et al (2005) Pathological cell-cell interactions elicited by a neuropathogenic form of mutant Huntingtin contribute to cortical pathogenesis in HD mice. Neuron 46:433–444PubMedCrossRefGoogle Scholar
  77. 77.
    Hagemann TL, Connor JX, Messing A (2006) Alexander disease-associated glial fibrillary acidic protein mutations in mice induce Rosenthal fiber formation and a white matter stress response. J Neurosci 26:11162–11173PubMedCrossRefGoogle Scholar
  78. 78.
    Hagemann TL, Paylor R, Messing A (2013) Deficits in adult neurogenesis, contextual fear conditioning, and spatial learning in a Gfap mutant mouse model of Alexander disease. J Neurosci 33:18698–18706PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Hagemann TL, Tian GF, Nedergaard M, Messing A (2008) Protective effects of αB-crystallin in mouse models of Alexander disease. Society for neurosciences abstract bookGoogle Scholar
  80. 80.
    Haj-Yasein NN, Jensen V, Vindedal GF, Gundersen GA, Klungland A, Ottersen OP, Hvalby O, Nagelhus EA (2011) Evidence that compromised K+ spatial buffering contributes to the epileptogenic effect of mutations in the human Kir4.1 gene (KCNJ10). Glia 59:1635–1642PubMedCrossRefGoogle Scholar
  81. 81.
    Halassa MM, Haydon PG (2010) Integrated brain circuits: astrocytic networks modulate neuronal activity and behavior. Annu Rev Physiol 72:335–355PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Hamby ME, Coppola G, Ao Y, Geschwind DH, Khakh BS, Sofroniew MV (2012) Inflammatory mediators alter the astrocyte transcriptome and calcium signaling elicited by multiple g-protein-coupled receptors. J Neurosci 32:14489–14510PubMedCentralPubMedCrossRefGoogle Scholar
  83. 83.
    Haroon F, Drogemuller K, Handel U, Brunn A, Reinhold D, Nishanth G, Mueller W, Trautwein C, Ernst M, Deckert M et al (2011) Gp130-dependent astrocytic survival is critical for the control of autoimmune central nervous system inflammation. J Immunol 186:6521–6531PubMedCrossRefGoogle Scholar
  84. 84.
    Hassel B, Tessler S, Faull RL, Emson PC (2008) Glutamate uptake is reduced in prefrontal cortex in Huntington’s disease. Neurochem Res 33:232–237PubMedCrossRefGoogle Scholar
  85. 85.
    Haydon PG, Carmignoto G (2006) Astrocyte control of synaptic transmission and neurovascular coupling. Physiol Rev 86:1009–1031PubMedCrossRefGoogle Scholar
  86. 86.
    Hazell AS (2009) Astrocytes are a major target in thiamine deficiency and Wernicke’s encephalopathy. Neurochem Int 55:129–135PubMedCrossRefGoogle Scholar
  87. 87.
    Henneberger C, Papouin T, Oliet SH, Rusakov DA (2010) Long-term potentiation depends on release of d-serine from astrocytes. Nature 463:232–236PubMedCentralPubMedCrossRefGoogle Scholar
  88. 88.
    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 28:7231–7243PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    Hertz L, Chen Y, Gibbs ME, Zang P, Peng L (2004) Astrocytic adrenoceptors: a major drug target in neurological and psychiatric disorders? Curr Drug Targets CNS Neurol Disord 3:239–267PubMedCrossRefGoogle Scholar
  90. 90.
    Hesdorffer DC, Logroscino G, Benn EK, Katri N, Cascino G, Hauser WA (2011) Estimating risk for developing epilepsy: a population-based study in Rochester, Minnesota. Neurology 76:23–27PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    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 32:121–130PubMedCrossRefGoogle Scholar
  92. 92.
    Hostenbach S, Cambron M, D’Haeseleer M, Kooijman R, De Keyser J (2014) Astrocyte loss and astrogliosis in neuroinflammatory disorders. Neurosci Lett 565:39–41PubMedCrossRefGoogle Scholar
  93. 93.
    Howell GR, Macalinao DG, Sousa GL, Walden M, Soto I, Kneeland SC, Barbay JM, King BL, Marchant JK, Hibbs M et al (2011) Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma. J Clin Investig 121:1429–1444PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Hsiao HY, Chen YC, Huang CH, Chen CC, Hsu YH, Chen HM, Chiu FL, Kuo HC, Chang C, Chern Y (2015) Aberrant astrocytes impair vascular reactivity in Huntington disease. Ann Neurol 78:178–192PubMedCrossRefGoogle Scholar
  95. 95.
    Hutchison ER, Kawamoto EM, Taub DD, Lal A, Abdelmohsen K, Zhang Y, Wood WH 3rd, Lehrmann E, Camandola S, Becker KG et al (2013) Evidence for miR-181 involvement in neuroinflammatory responses of astrocytes. Glia 61:1018–1028PubMedCentralPubMedCrossRefGoogle Scholar
  96. 96.
    Iadecola C, Nedergaard M (2007) Glial regulation of the cerebral microvasculature. Nat Neurosci 10:1369–1376PubMedCrossRefGoogle Scholar
  97. 97.
    Ingelsson M, Fukumoto H, Newell KL, Growdon JH, Hedley-Whyte ET, Frosch MP, Albert MS, Hyman BT, Irizarry MC (2004) Early Aβ accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology 62:925–931PubMedCrossRefGoogle Scholar
  98. 98.
    Iwaki T, Kume-Iwaki A, Liem RK, Goldman JE (1989) α B-crystallin is expressed in non-lenticular tissues and accumulates in Alexander’s disease brain. Cell 57:71–78PubMedCrossRefGoogle Scholar
  99. 99.
    Jackrel ME, DeSantis ME, Martinez BA, Castellano LM, Stewart RM, Caldwell KA, Caldwell GA, Shorter J (2014) Potentiated Hsp104 variants antagonize diverse proteotoxic misfolding events. Cell 156:170–182PubMedCentralPubMedCrossRefGoogle Scholar
  100. 100.
    Jany PL, Hagemann TL, Messing A (2013) GFAP expression as an indicator of disease severity in mouse models of Alexander disease. ASN Neuro 5:e00109PubMedCentralPubMedCrossRefGoogle Scholar
  101. 101.
    Jarlestedt K, Rousset CI, Faiz M, Wilhelmsson U, Stahlberg A, Sourkova H, Pekna M, Mallard C, Hagberg H, Pekny M (2010) Attenuation of reactive gliosis does not affect infarct volume in neonatal hypoxic-ischemic brain injury in mice. PLoS One 5:e10397PubMedCentralPubMedCrossRefGoogle Scholar
  102. 102.
    Jing R, Wilhelmsson U, Goodwill W, Li L, Pan Y, Pekny M, Skalli O (2007) Synemin is expressed in reactive astrocytes in neurotrauma and interacts differentially with vimentin and GFAP intermediate filament networks. J Cell Sci 120:1267–1277PubMedCrossRefGoogle Scholar
  103. 103.
    Jo S, Yarishkin O, Hwang YJ, Chun YE, Park M, Woo DH, Bae JY, Kim T, Lee J, Chun H et al (2014) GABA from reactive astrocytes impairs memory in mouse models of Alzheimer’s disease. Nat Med 20:886–896PubMedCrossRefGoogle Scholar
  104. 104.
    Kamphuis W, Kooijman L, Orre M, Stassen O, Pekny M, Hol EM (2015) GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer’s disease. Glia 63:1036–1056PubMedCrossRefGoogle Scholar
  105. 105.
    Kamphuis W, Mamber C, Moeton M, Kooijman L, Sluijs JA, Jansen AH, Verveer M, de Groot LR, Smith VD, Rangarajan S et al (2012) GFAP isoforms in adult mouse brain with a focus on neurogenic astrocytes and reactive astrogliosis in mouse models of Alzheimer disease. PLoS One 7:e42823PubMedCentralPubMedCrossRefGoogle Scholar
  106. 106.
    Kamphuis W, Middeldorp J, Kooijman L, Sluijs JA, Kooi EJ, Moeton M, Freriks M, Mizee MR, Hol EM (2014) Glial fibrillary acidic protein isoform expression in plaque related astrogliosis in Alzheimer’s disease. Neurobiol Aging 35:492–510PubMedCrossRefGoogle Scholar
  107. 107.
    Kamphuis W, Orre M, Kooijman L, Dahmen M, Hol EM (2012) Differential cell proliferation in the cortex of the APPswePS1dE9 Alzheimer’s disease mouse model. Glia 60:615–629PubMedCrossRefGoogle Scholar
  108. 108.
    Kanekiyo T, Xu H, Bu G (2014) ApoE and Aβ in Alzheimer’s disease: accidental encounters or partners? Neuron 81:740–754PubMedCentralPubMedCrossRefGoogle Scholar
  109. 109.
    Kang W, Hebert JM (2011) Signaling pathways in reactive astrocytes, a genetic perspective. Mol Neurobiol 43:147–154PubMedCentralPubMedCrossRefGoogle Scholar
  110. 110.
    Karch CM, Cruchaga C, Goate AM (2014) Alzheimer’s disease genetics: from the bench to the clinic. Neuron 83:11–26PubMedCentralPubMedCrossRefGoogle Scholar
  111. 111.
    Kashon ML, Ross GW, O’Callaghan JP, Miller DB, Petrovitch H, Burchfiel CM, Sharp DS, Markesbery WR, Davis DG, Hardman J et al (2004) Associations of cortical astrogliosis with cognitive performance and dementia status. J Alzheimer’s Dis 6:595–604 (discussion 673–581) Google Scholar
  112. 112.
    Kato Y, Maruyama W, Naoi M, Hashizume Y, Osawa T (1998) Immunohistochemical detection of dityrosine in lipofuscin pigments in the aged human brain. FEBS Lett 439:231–234PubMedCrossRefGoogle Scholar
  113. 113.
    Kerr BJ, Patterson PH (2004) Potent pro-inflammatory actions of leukemia inhibitory factor in the spinal cord of the adult mouse. Exp Neurol 188:391–407PubMedCrossRefGoogle Scholar
  114. 114.
    Kettenmann H, Kirchhoff F, Verkhratsky A (2013) Microglia: new roles for the synaptic stripper. Neuron 77:10–18PubMedCrossRefGoogle Scholar
  115. 115.
    Kheirbek MA, Tannenholz L, Hen R (2012) NR2B-dependent plasticity of adult-born granule cells is necessary for context discrimination. J Neurosci 32:8696–8702PubMedCentralPubMedCrossRefGoogle Scholar
  116. 116.
    Kinouchi R, Takeda M, Yang L, Wilhelmsson U, Lundkvist A, Pekny M, Chen DF (2003) Robust neural integration from retinal transplants in mice deficient in GFAP and vimentin. Nat Neurosci 6:863–868PubMedCrossRefGoogle Scholar
  117. 117.
    Klein MA, Moller JC, Jones LL, Bluethmann H, Kreutzberg GW, Raivich G (1997) Impaired neuroglial activation in interleukin-6 deficient mice. Glia 19:227–233PubMedCrossRefGoogle Scholar
  118. 118.
    Kraft AW, Hu X, Yoon H, Yan P, Xiao Q, Wang Y, Gil SC, Brown J, Wilhelmsson U, Restivo JL et al (2013) Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice. FASEB J 27:187–198PubMedCentralPubMedCrossRefGoogle Scholar
  119. 119.
    Kuchibhotla KV, Lattarulo CR, Hyman BT, Bacskai BJ (2009) Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science 323:1211–1215PubMedCentralPubMedCrossRefGoogle Scholar
  120. 120.
    Kucukdereli H, Allen NJ, Lee AT, Feng A, Ozlu MI, Conatser LM, Chakraborty C, Workman G, Weaver M, Sage EH et al (2011) Control of excitatory CNS synaptogenesis by astrocyte-secreted proteins Hevin and SPARC. Proc Natl Acad Sci 108:E440–E449PubMedCentralPubMedCrossRefGoogle Scholar
  121. 121.
    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 221:252–262PubMedCentralPubMedCrossRefGoogle Scholar
  122. 122.
    Kunze A, Congreso MR, Hartmann C, Wallraff-Beck A, Huttmann K, Bedner P, Requardt R, Seifert G, Redecker C, Willecke K et al (2009) Connexin expression by radial glia-like cells is required for neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci 106:11336–11341PubMedCentralPubMedCrossRefGoogle Scholar
  123. 123.
    LaPash Daniels CM, Austin EV, Rockney DE, Jacka EM, Hagemann TL, Johnson DA, Johnson JA, Messing A (2012) Beneficial effects of Nrf2 overexpression in a mouse model of Alexander disease. J Neurosci 32:10507–10515PubMedCentralPubMedCrossRefGoogle Scholar
  124. 124.
    Lebkuechner I, Wilhelmsson U, Mollerstrom E, Pekna M, Pekny M (2015) Heterogeneity of Notch signaling in astrocytes and the effects of GFAP and vimentin deficiency. J Neurochem 135:234–248PubMedCrossRefGoogle Scholar
  125. 125.
    Lee H, McKeon RJ, Bellamkonda RV (2010) Sustained delivery of thermostabilized chABC enhances axonal sprouting and functional recovery after spinal cord injury. Proc Natl Acad Sci 107:3340–3345PubMedCentralPubMedCrossRefGoogle Scholar
  126. 126.
    Lee W, Reyes RC, Gottipati MK, Lewis K, Lesort M, Parpura V, Gray M (2013) Enhanced Ca2+-dependent glutamate release from astrocytes of the BACHD Huntington’s disease mouse model. Neurobiol Dis 58:192–199PubMedCentralPubMedCrossRefGoogle Scholar
  127. 127.
    Levison SW, Jiang FJ, Stoltzfus OK, Ducceschi MH (2000) IL-6-type cytokines enhance epidermal growth factor-stimulated astrocyte proliferation. Glia 32:328–337PubMedCrossRefGoogle Scholar
  128. 128.
    Lepekhin EA, Eliasson C, Berthold CH, Berezin V, Bock E, Pekny M (2001) Intermediate filaments regulate astrocyte motility. J Neurochem 79:617–625PubMedCrossRefGoogle Scholar
  129. 129.
    Li C, Zhao R, Gao K, Wei Z, Yin MY, Lau LT, Chui D, Hoi Yu AC (2011) Astrocytes: implications for neuroinflammatory pathogenesis of Alzheimer’s disease. Curr Alzheimer Res 8:67–80PubMedCrossRefGoogle Scholar
  130. 130.
    Li L, Lundkvist A, Andersson D, Wilhelmsson U, Nagai N, Pardo AC, Nodin C, Stahlberg A, Aprico K, Larsson K et al (2008) Protective role of reactive astrocytes in brain ischemia. J Cereb Blood Flow Metab 28:468–481PubMedCrossRefGoogle Scholar
  131. 131.
    Li Y, Cheng D, Cheng R, Zhu X, Wan T, Liu J, Zhang R (2014) Mechanisms of U87 astrocytoma cell uptake and trafficking of monomeric versus protofibril Alzheimer’s disease amyloid-beta proteins. PLoS One 9:e99939PubMedCentralPubMedCrossRefGoogle Scholar
  132. 132.
    Lian H, Yang L, Cole A, Sun L, Chiang AC, Fowler SW, Shim DJ, Rodriguez-Rivera J, Taglialatela G, Jankowsky JL et al (2015) NFkappaB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer’s disease. Neuron 85:101–115PubMedCentralPubMedCrossRefGoogle Scholar
  133. 133.
    Liauw J, Hoang S, Choi M, Eroglu C, Choi M, Sun GH, Percy M, Wildman-Tobriner B, Bliss T, Guzman RG et al (2008) Thrombospondins 1 and 2 are necessary for synaptic plasticity and functional recovery after stroke. J Cereb Blood Flow Metab 28:1722–1732PubMedCrossRefGoogle Scholar
  134. 134.
    Lie DC, Colamarino SA, Song HJ, Desire L, Mira H, Consiglio A, Lein ES, Jessberger S, Lansford H, Dearie AR et al (2005) Wnt signalling regulates adult hippocampal neurogenesis. Nature 437:1370–1375PubMedCrossRefGoogle Scholar
  135. 135.
    Lievens JC, Woodman B, Mahal A, Spasic-Boscovic O, Samuel D, Kerkerian-Le Goff L, Bates GP (2001) Impaired glutamate uptake in the R6 Huntington’s disease transgenic mice. Neurobiol Dis 8:807–821PubMedCrossRefGoogle Scholar
  136. 136.
    Lim D, Ronco V, Grolla AA, Verkhratsky A, Genazzani AA (2014) Glial calcium signalling in Alzheimer’s disease. Rev Physiol Biochem Pharmacol 167:45–65PubMedGoogle Scholar
  137. 137.
    Lin CH, Tallaksen-Greene S, Chien WM, Cearley JA, Jackson WS, Crouse AB, Ren S, Li XJ, Albin RL, Detloff PJ (2001) Neurological abnormalities in a knock-in mouse model of Huntington’s disease. Hum Mol Genet 10:137–144PubMedCrossRefGoogle Scholar
  138. 138.
    Loscher W, Schmidt D (2011) Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma. Epilepsia 52:657–678PubMedCrossRefGoogle Scholar
  139. 139.
    Lu YB, Iandiev I, Hollborn M, Korber N, Ulbricht E, Hirrlinger PG, Pannicke T, Wei EQ, Bringmann A, Wolburg H et al (2011) Reactive glial cells: increased stiffness correlates with increased intermediate filament expression. FASEB J 25:624–631PubMedCrossRefGoogle Scholar
  140. 140.
    Lucca U, Tettamanti M, Forloni G, Spagnoli A (1994) Nonsteroidal antiinflammatory drug use in Alzheimer’s disease. Biol Psychiatry 36:854–856PubMedCrossRefGoogle Scholar
  141. 141.
    Lundkvist A, Reichenbach A, Betsholtz C, Carmeliet P, Wolburg H, Pekny M (2004) Under stress, the absence of intermediate filaments from Muller cells in the retina has structural and functional consequences. J Cell Sci 117:3481–3488PubMedCrossRefGoogle Scholar
  142. 142.
    Macauley SL, Pekny M, Sands MS (2011) The role of attenuated astrocyte activation in infantile neuronal ceroid lipofuscinosis. J Neurosci 31:15575–15585PubMedCentralPubMedCrossRefGoogle Scholar
  143. 143.
    Malarkey EB, Parpura V (2008) Mechanisms of glutamate release from astrocytes. Neurochem Int 52:142–154PubMedCentralPubMedCrossRefGoogle Scholar
  144. 144.
    Menet V, Prieto M, Privat A, Giménez y Ribotta M (2003) Axonal plasticity and functional recovery after spinal cord injury in mice deficient in both glial fibrillary acidic protein and vimentin genes. Proc Natl Acad Sci 100:8999–9004PubMedCentralPubMedCrossRefGoogle Scholar
  145. 145.
    Messing A, Brenner M, Feany MB, Nedergaard M, Goldman JE (2012) Alexander disease. J Neurosci 32:5017–5023PubMedCentralPubMedCrossRefGoogle Scholar
  146. 146.
    Messing A, Head MW, Galles K, Galbreath EJ, Goldman JE, Brenner M (1998) Fatal encephalopathy with astrocyte inclusions in GFAP transgenic mice. Am J Pathol 152:391–398PubMedCentralPubMedGoogle Scholar
  147. 147.
    Middeldorp J, Hol EM (2011) GFAP in health and disease. Prog Neurobiol 93:421–443PubMedCrossRefGoogle Scholar
  148. 148.
    Mori H, Hanada R, Hanada T, Aki D, Mashima R, Nishinakamura H, Torisu T, Chien KR, Yasukawa H, Yoshimura A (2004) Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat Med 10:739–743PubMedCrossRefGoogle Scholar
  149. 149.
    Mosconi L, Pupi A, De Leon MJ (2008) Brain glucose hypometabolism and oxidative stress in preclinical Alzheimer’s disease. Ann N Y Acad Sci 1147:180–195PubMedCentralPubMedCrossRefGoogle Scholar
  150. 150.
    Mrak RE, Griffinbc WS (2001) The role of activated astrocytes and of the neurotrophic cytokine S100B in the pathogenesis of Alzheimer’s disease. Neurobiol Aging 22:915–922PubMedCrossRefGoogle Scholar
  151. 151.
    Myer DJ, Gurkoff GG, Lee SM, Hovda DA, Sofroniew MV (2006) Essential protective roles of reactive astrocytes in traumatic brain injury. Brain 129:2761–2772PubMedCrossRefGoogle Scholar
  152. 152.
    Nagler K, Mauch DH, Pfrieger FW (2001) Glia-derived signals induce synapse formation in neurones of the rat central nervous system. J Physiol 533:665–679PubMedCentralPubMedCrossRefGoogle Scholar
  153. 153.
    Nakazawa T, Takeda M, Lewis GP, Cho KS, Jiao J, Wilhelmsson U, Fisher SK, Pekny M, Chen DF, Miller JW (2007) Attenuated glial reactions and photoreceptor degeneration after retinal detachment in mice deficient in glial fibrillary acidic protein and vimentin. Invest Ophthalmol Vis Sci 48:2760–2768PubMedCentralPubMedCrossRefGoogle Scholar
  154. 154.
    Nawashiro H, Messing A, Azzam N, Brenner M (1998) Mice lacking GFAP are hypersensitive to traumatic cerebrospinal injury. NeuroReport 9:1691–1696PubMedCrossRefGoogle Scholar
  155. 155.
    Nedergaard M, Ransom B, Goldman SA (2003) New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci 26:523–530PubMedCrossRefGoogle Scholar
  156. 156.
    Niciu MJ, Henter ID, Sanacora G, Zarate CA Jr (2014) Glial abnormalities in substance use disorders and depression: does shared glutamatergic dysfunction contribute to comorbidity? World J Biol Psychiatry 15:2–16PubMedCentralPubMedCrossRefGoogle Scholar
  157. 157.
    Oberheim NA, Wang X, Goldman S, Nedergaard M (2006) Astrocytic complexity distinguishes the human brain. Trends Neurosci 29:547–553PubMedCrossRefGoogle Scholar
  158. 158.
    Okada S, Nakamura M, Katoh H, Miyao T, Shimazaki T, Ishii K, Yamane J, Yoshimura A, Iwamoto Y, Toyama Y et al (2006) Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. Nat Med 12:829–834PubMedCrossRefGoogle Scholar
  159. 159.
    Olabarria M, Noristani HN, Verkhratsky A, Rodriguez JJ (2011) Age-dependent decrease in glutamine synthetase expression in the hippocampal astroglia of the triple transgenic Alzheimer’s disease mouse model: mechanism for deficient glutamatergic transmission? Mol Neurodegener 6:55PubMedCentralPubMedCrossRefGoogle Scholar
  160. 160.
    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 58:831–838PubMedGoogle Scholar
  161. 161.
    Orre M, Kamphuis W, Dooves S, Kooijman L, Chan ET, Kirk CJ, Dimayuga Smith V, Koot S, Mamber C, Jansen AH et al (2013) Reactive glia show increased immunoproteasome activity in Alzheimer’s disease. Brain 136:1415–1431PubMedCrossRefGoogle Scholar
  162. 162.
    Orre M, Kamphuis W, Osborn LM, Jansen AH, Kooijman L, Bossers K, Hol EM (2014) Isolation of glia from Alzheimer’s mice reveals inflammation and dysfunction. Neurobiol Aging 35:2746–2760PubMedCrossRefGoogle Scholar
  163. 163.
    Orre M, Kamphuis W, Osborn LM, Melief J, Kooijman L, Huitinga I, Klooster J, Bossers K, Hol EM (2014) Acute isolation and transcriptome characterization of cortical astrocytes and microglia from young and aged mice. Neurobiol Aging 35:1–14PubMedCrossRefGoogle Scholar
  164. 164.
    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 13:584–591PubMedCentralPubMedCrossRefGoogle Scholar
  165. 165.
    Overman JJ, Clarkson AN, Wanner IB, Overman WT, Eckstein I, Maguire JL, Dinov ID, Toga AW, Carmichael ST (2012) A role for ephrin-A5 in axonal sprouting, recovery, and activity-dependent plasticity after stroke. Proc Natl Acad Sci 109:E2230–E2239PubMedCentralPubMedCrossRefGoogle Scholar
  166. 166.
    Pannasch U, Vargova L, Reingruber J, Ezan P, Holcman D, Giaume C, Sykova E, Rouach N (2011) Astroglial networks scale synaptic activity and plasticity. Proc Natl Acad Sci 108:8467–8472PubMedCentralPubMedCrossRefGoogle Scholar
  167. 167.
    Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, Giustetto M, Ferreira TA, Guiducci E, Dumas L et al (2011) Synaptic pruning by microglia is necessary for normal brain development. Science 333:1456–1458PubMedCrossRefGoogle Scholar
  168. 168.
    Parpura V, Grubisic V, Verkhratsky A (2011) Ca2+ sources for the exocytotic release of glutamate from astrocytes. Biochim Biophys Acta 1813:984–991PubMedCrossRefGoogle Scholar
  169. 169.
    Parpura V, Heneka MT, Montana V, Oliet SH, Schousboe A, Haydon PG, Stout RF Jr, Spray DC, Reichenbach A, Pannicke T et al (2012) Glial cells in (patho)physiology. J Neurochem 121:4–27PubMedCentralPubMedCrossRefGoogle Scholar
  170. 170.
    Pekna M, Pekny M, Nilsson M (2012) Modulation of neural plasticity as a basis for stroke rehabilitation. Stroke 43:2819–2828PubMedCrossRefGoogle Scholar
  171. 171.
    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 145:503–514PubMedCentralPubMedCrossRefGoogle Scholar
  172. 172.
    Pekny M, Nilsson M (2005) Astrocyte activation and reactive gliosis. Glia 50:427–434PubMedCrossRefGoogle Scholar
  173. 173.
    Pekny M, Pekna M (2004) Astrocyte intermediate filaments in CNS pathologies and regeneration. J Pathol 204:428–437PubMedCrossRefGoogle Scholar
  174. 174.
    Pekny M, Pekna M (2014) Astrocyte reactivity and reactive astrogliosis: costs and benefits. Physiol Rev 94:1077–1098PubMedCrossRefGoogle Scholar
  175. 175.
    Pekny M, Wilhelmsson U, Pekna M (2014) The dual role of astrocyte activation and reactive gliosis. Neurosci Lett 565C:30–38CrossRefGoogle Scholar
  176. 176.
    Pekny T, Faiz M, Wilhelmsson U, Curtis MA, Matej R, Skalli O, Pekny M (2014) Synemin is expressed in reactive astrocytes and Rosenthal fibers in Alexander disease. APMIS 122:76–80PubMedCrossRefGoogle Scholar
  177. 177.
    Perez-Alcazar M, Daborg J, Stokowska A, Wasling P, Bjorefeldt A, Kalm M, Zetterberg H, Carlstrom KE, Blomgren K, Ekdahl CT et al (2014) Altered cognitive performance and synaptic function in the hippocampus of mice lacking C3. Exp Neurol 253:154–164PubMedCrossRefGoogle Scholar
  178. 178.
    Peters O, Schipke CG, Philipps A, Haas B, Pannasch U, Wang LP, Benedetti B, Kingston AE, Kettenmann H (2009) Astrocyte function is modified by Alzheimer’s disease-like pathology in aged mice. J Alzheimer’s Dis 18:177–189Google Scholar
  179. 179.
    Potokar M, Kreft M, Li L, Daniel Andersson J, Pangrsic T, Chowdhury HH, Pekny M, Zorec R (2007) Cytoskeleton and vesicle mobility in astrocytes. Traffic (Copenhagen, Denmark) 8:12–20Google Scholar
  180. 180.
    Potokar M, Stenovec M, Gabrijel M, Li L, Kreft M, Grilc S, Pekny M, Zorec R (2010) Intermediate filaments attenuate stimulation-dependent mobility of endosomes/lysosomes in astrocytes. Glia 58:1208–1219PubMedGoogle Scholar
  181. 181.
    Rabchevsky AG, Weinitz JM, Coulpier M, Fages C, Tinel M, Junier MP (1998) A role for transforming growth factor alpha as an inducer of astrogliosis. J Neurosci 18:10541–10552PubMedGoogle Scholar
  182. 182.
    Rajkowska G, Stockmeier CA (2013) Astrocyte pathology in major depressive disorder: insights from human postmortem brain tissue. Curr Drug Targets 14:1225–1236PubMedCentralPubMedCrossRefGoogle Scholar
  183. 183.
    Reines SA, Block GA, Morris JC, Liu G, Nessly ML, Lines CR, Norman BA, Baranak CC, Rofecoxib Protocol 091 Study G (2004) Rofecoxib: no effect on Alzheimer’s disease in a 1-year, randomized, blinded, controlled study. Neurology 62:66–71Google Scholar
  184. 184.
    Renault-Mihara F, Okada S, Shibata S, Nakamura M, Toyama Y, Okano H (2008) Spinal cord injury: emerging beneficial role of reactive astrocytes’ migration. Int J Biochem Cell Biol 40:1649–1653PubMedCrossRefGoogle Scholar
  185. 185.
    Robel S, Berninger B, Gotz M (2011) The stem cell potential of glia: lessons from reactive gliosis. Nat Rev Neurosci 12:88–104PubMedCrossRefGoogle Scholar
  186. 186.
    Rodriguez-Arellano JJ, Parpura V, Zorec R, Verkhratsky A (2015) Astrocytes in physiological aging and Alzheimer’s disease. Neuroscience. doi: 10.1016/j.neuroscience.2015.01.007
  187. 187.
    Rolls A, Shechter R, Schwartz M (2009) The bright side of the glial scar in CNS repair. Nat Rev Neurosci 10:235–241PubMedCrossRefGoogle Scholar
  188. 188.
    Ronco V, Grolla AA, Glasnov TN, Canonico PL, Verkhratsky A, Genazzani AA, Lim D (2014) Differential deregulation of astrocytic calcium signalling by amyloid-β, TNFα, IL-1β and LPS. Cell Calcium 55:219–229PubMedCrossRefGoogle Scholar
  189. 189.
    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 15:1691–1700PubMedCrossRefGoogle Scholar
  190. 190.
    Rouach N, Koulakoff A, Abudara V, Willecke K, Giaume C (2008) Astroglial metabolic networks sustain hippocampal synaptic transmission. Science 322:1551–1555PubMedCrossRefGoogle Scholar
  191. 191.
    Sahay A, Scobie KN, Hill AS, O’Carroll CM, Kheirbek MA, Burghardt NS, Fenton AA, Dranovsky A, Hen R (2011) Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 472:466–470PubMedCentralPubMedCrossRefGoogle Scholar
  192. 192.
    Samuel W, Masliah E, Hill LR, Butters N, Terry R (1994) Hippocampal connectivity and Alzheimer’s dementia: effects of synapse loss and tangle frequency in a two-component model. Neurology 44:2081–2088PubMedCrossRefGoogle Scholar
  193. 193.
    Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, Ransohoff RM, Greenberg ME, Barres BA, Stevens B (2012) Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74:691–705PubMedCentralPubMedCrossRefGoogle Scholar
  194. 194.
    Schwarcz R, Hunter CA (2007) Toxoplasma gondii and schizophrenia: linkage through astrocyte-derived kynurenic acid? Schizophr Bull 33:652–653PubMedCentralPubMedCrossRefGoogle Scholar
  195. 195.
    Seifert G, Huttmann K, Binder DK, Hartmann C, Wyczynski A, Neusch C, Steinhauser C (2009) Analysis of astroglial K+ channel expression in the developing hippocampus reveals a predominant role of the Kir4.1 subunit. J Neurosci 29:7474–7488PubMedCrossRefGoogle Scholar
  196. 196.
    Seifert G, Schilling K, Steinhauser C (2006) Astrocyte dysfunction in neurological disorders: a molecular perspective. Nat Rev Neurosci 7:194–206PubMedCrossRefGoogle Scholar
  197. 197.
    Seifert G, Steinhauser C (2013) Neuron-astrocyte signaling and epilepsy. Exp Neurol 244:4–10PubMedCrossRefGoogle Scholar
  198. 198.
    Seri B, Garcia-Verdugo JM, McEwen BS, Alvarez-Buylla A (2001) Astrocytes give rise to new neurons in the adult mammalian hippocampus. J Neurosci 21:7153–7160PubMedGoogle Scholar
  199. 199.
    Settembre C, De Cegli R, Mansueto G, Saha PK, Vetrini F, Visvikis O, Huynh T, Carissimo A, Palmer D, Klisch TJ et al (2013) TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat Cell Biol 15:647–658PubMedCentralPubMedCrossRefGoogle Scholar
  200. 200.
    Settembre C, Di Malta C, Polito VA, Garcia Arencibia M, Vetrini F, Erdin S, Erdin SU, Huynh T, Medina D, Colella P et al (2011) TFEB links autophagy to lysosomal biogenesis. Science 332:1429–1433PubMedCentralPubMedCrossRefGoogle Scholar
  201. 201.
    Sharma K, Selzer ME, Li S (2012) Scar-mediated inhibition and CSPG receptors in the CNS. Exp Neurol 237:370–378PubMedCrossRefGoogle Scholar
  202. 202.
    Shi Q, Colodner KJ, Matousek SB, Merry K, Hong S, Kenison JE, Frost JL, Le KX, Li S, Dodart JC et al (2015) Complement C3-deficient mice fail to display age-related hippocampal decline. J Neurosci 35:13029–13042PubMedCrossRefGoogle Scholar
  203. 203.
    Shinjyo N, de Pablo Y, Pekny M, Pekna M (2015) Complement peptide C3a promotes astrocyte survival in response to ischemic stress. Mol Neurobiol [Epub ahead of print] Google Scholar
  204. 204.
    Shinjyo N, Stahlberg A, Dragunow M, Pekny M, Pekna M (2009) Complement-derived anaphylatoxin C3a regulates in vitro differentiation and migration of neural progenitor cells. Stem Cells 27:2824–2832PubMedCrossRefGoogle Scholar
  205. 205.
    Silver J, Miller JH (2004) Regeneration beyond the glial scar. Nat Rev Neurosci 5:146–156PubMedCrossRefGoogle Scholar
  206. 206.
    Simonato M, Loscher W, Cole AJ, Dudek FE, Engel J Jr, Kaminski RM, Loeb JA, Scharfman H, Staley KJ, Velisek L et al (2012) Finding a better drug for epilepsy: preclinical screening strategies and experimental trial design. Epilepsia 53:1860–1867PubMedCentralPubMedCrossRefGoogle Scholar
  207. 207.
    Simpson JE, Ince PG, Lace G, Forster G, Shaw PJ, Matthews F, Savva G, Brayne C, Wharton SB, Function MRCC et al (2010) Astrocyte phenotype in relation to Alzheimer-type pathology in the ageing brain. Neurobiol Aging 31:578–590PubMedCrossRefGoogle Scholar
  208. 208.
    Sirko S, Behrendt G, Johansson PA, Tripathi P, Costa M, Bek S, Heinrich C, Tiedt S, Colak D, Dichgans M et al (2013) Reactive glia in the injured brain acquire stem cell properties in response to sonic hedgehog. [corrected]. Cell Stem Cell 12:426–439PubMedCrossRefGoogle Scholar
  209. 209.
    Sofroniew MV (2014) Astrogliosis. Cold Spring Harb Perspect Biol 7:a020420PubMedCrossRefGoogle Scholar
  210. 210.
    Sofroniew MV (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 32:638–647PubMedCentralPubMedCrossRefGoogle Scholar
  211. 211.
    Sofroniew MV (2014) Multiple roles for astrocytes as effectors of cytokines and inflammatory mediators. Neuroscientist 20:160–172PubMedCrossRefGoogle Scholar
  212. 212.
    Sofroniew MV, Bush TG, Blumauer N, Lawrence K, Mucke L, Johnson MH (1999) Genetically-targeted and conditionally-regulated ablation of astroglial cells in the central, enteric and peripheral nervous systems in adult transgenic mice. Brain Res 835:91–95PubMedCrossRefGoogle Scholar
  213. 213.
    Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35PubMedCentralPubMedCrossRefGoogle Scholar
  214. 214.
    Song H, Stevens CF, Gage FH (2002) Astroglia induce neurogenesis from adult neural stem cells. Nature 417:39–44PubMedCrossRefGoogle Scholar
  215. 215.
    Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB, Bostrom E, Westerlund I, Vial C, Buchholz BA et al (2013) Dynamics of hippocampal neurogenesis in adult humans. Cell 153:1219–1227PubMedCentralPubMedCrossRefGoogle Scholar
  216. 216.
    Spence RD, Hamby ME, Umeda E, Itoh N, Du S, Wisdom AJ, Cao Y, Bondar G, Lam J, Ao Y et al (2011) Neuroprotection mediated through estrogen receptor-α in astrocytes. Proc Natl Acad Sci 108:8867–8872PubMedCentralPubMedCrossRefGoogle Scholar
  217. 217.
    Spence RD, Wisdom AJ, Cao Y, Hill HM, Mongerson CR, Stapornkul B, Itoh N, Sofroniew MV, Voskuhl RR (2013) Estrogen mediates neuroprotection and anti-inflammatory effects during EAE through ERalpha signaling on astrocytes but not through ERbeta signaling on astrocytes or neurons. J Neurosci 33:10924–10933PubMedCentralPubMedCrossRefGoogle Scholar
  218. 218.
    Sriram K, Benkovic SA, Hebert MA, Miller DB, O’Callaghan JP (2004) Induction of gp130-related cytokines and activation of JAK2/STAT3 pathway in astrocytes precedes up-regulation of glial fibrillary acidic protein in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of neurodegeneration: key signaling pathway for astrogliosis in vivo? J Biol Chem 279:19936–19947PubMedCrossRefGoogle Scholar
  219. 219.
    Stahlberg A, Andersson D, Aurelius J, Faiz M, Pekna M, Kubista M, Pekny M (2011) Defining cell populations with single-cell gene expression profiling: correlations and identification of astrocyte subpopulations. Nucleic Acids Res 39:e24PubMedCentralPubMedCrossRefGoogle Scholar
  220. 220.
    Steinhauser C, Seifert G, Bedner P (2012) Astrocyte dysfunction in temporal lobe epilepsy: K+ channels and gap junction coupling. Glia 60:1192–1202PubMedCrossRefGoogle Scholar
  221. 221.
    Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, Micheva KD, Mehalow AK, Huberman AD, Stafford B et al (2007) The classical complement cascade mediates CNS synapse elimination. Cell 131:1164–1178PubMedCrossRefGoogle Scholar
  222. 222.
    Suzuki A, Stern SA, Bozdagi O, Huntley GW, Walker RH, Magistretti PJ, Alberini CM (2011) Astrocyte-neuron lactate transport is required for long-term memory formation. Cell 144:810–823PubMedCentralPubMedCrossRefGoogle Scholar
  223. 223.
    Tanaka KF, Takebayashi H, Yamazaki Y, Ono K, Naruse M, Iwasato T, Itohara S, Kato H, Ikenaka K (2007) Murine model of Alexander disease: analysis of GFAP aggregate formation and its pathological significance. Glia 55:617–631PubMedCrossRefGoogle Scholar
  224. 224.
    Tao J, Wu H, Lin Q, Wei W, Lu XH, Cantle JP, Ao Y, Olsen RW, Yang XW, Mody I et al (2011) Deletion of astroglial dicer causes non-cell-autonomous neuronal dysfunction and degeneration. J Neurosci 31:8306–8319PubMedCentralPubMedCrossRefGoogle Scholar
  225. 225.
    Terry RD (2000) Cell death or synaptic loss in Alzheimer disease. J Neuropathol Exp Neurol 59:1118–1119PubMedCrossRefGoogle Scholar
  226. 226.
    Tian R, Gregor M, Wiche G, Goldman JE (2006) Plectin regulates the organization of glial fibrillary acidic protein in Alexander disease. Am J Pathol 168:888–897PubMedCentralPubMedCrossRefGoogle Scholar
  227. 227.
    Tian R, Wu X, Hagemann TL, Sosunov AA, Messing A, McKhann GM, Goldman JE (2010) Alexander disease mutant glial fibrillary acidic protein compromises glutamate transport in astrocytes. J Neuropathol Exp Neurol 69:335–345PubMedCentralPubMedCrossRefGoogle Scholar
  228. 228.
    Tong X, Ao Y, Faas GC, Nwaobi SE, Xu J, Haustein MD, Anderson MA, Mody I, Olsen ML, Sofroniew MV et al (2014) Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington’s disease model mice. Nat Neurosci 17:694–703PubMedCentralPubMedCrossRefGoogle Scholar
  229. 229.
    Tremblay ME, Lowery RL, Majewska AK (2010) Microglial interactions with synapses are modulated by visual experience. PLoS Biol 8:e1000527PubMedCentralPubMedCrossRefGoogle Scholar
  230. 230.
    Vardjan N, Gabrijel M, Potokar M, Svajger U, Kreft M, Jeras M, de Pablo Y, Faiz M, Pekny M, Zorec R (2012) IFN-γ-induced increase in the mobility of MHC class II compartments in astrocytes depends on intermediate filaments. J Neuroinflamm 9:144Google Scholar
  231. 231.
    Veeraraghavalu K, Zhang C, Zhang X, Tanzi RE, Sisodia SS (2014) Age-dependent, non-cell-autonomous deposition of amyloid from synthesis of beta-amyloid by cells other than excitatory neurons. J Neurosci 34:3668–3673PubMedCentralPubMedCrossRefGoogle Scholar
  232. 232.
    Verardo MR, Lewis GP, Takeda M, Linberg KA, Byun J, Luna G, Wilhelmsson U, Pekny M, Chen DF, Fisher SK (2008) Abnormal reactivity of muller cells after retinal detachment in mice deficient in GFAP and vimentin. Invest Ophthalmol Vis Sci 49:3659–3665PubMedCentralPubMedCrossRefGoogle Scholar
  233. 233.
    Verghese PB, Castellano JM, Holtzman DM (2011) Apolipoprotein E in Alzheimer’s disease and other neurological disorders. Lancet Neurol 10:241–252PubMedCentralPubMedCrossRefGoogle Scholar
  234. 234.
    Verkhratsky A, Marutle A, Rodriguez-Arellano JJ, Nordberg A (2014) Glial asthenia and functional paralysis: a new perspective on neurodegeneration and Alzheimer’s disease. Neuroscientist. pii: 1073858414547132Google Scholar
  235. 235.
    Verkhratsky A, Nedergaard M (2014) Astroglial cradle in the life of the synapse. Philos Trans R Soc Lond B Biol Sci 369:20130595PubMedCentralPubMedCrossRefGoogle Scholar
  236. 236.
    Verkhratsky A, Parpura V, Pekna M, Pekny M, Sofroniew M (2014) Glia in the pathogenesis of neurodegenerative diseases. Biochem Soc Trans 42:1291–1301PubMedCrossRefGoogle Scholar
  237. 237.
    Verkhratsky A, Rodriguez JJ, Parpura V (2013) Astroglia in neurological diseases. Fut Neurol 8:149–158CrossRefGoogle Scholar
  238. 238.
    Verkhratsky A, Rodriguez JJ, Steardo L (2014) Astrogliopathology: a central element of neuropsychiatric diseases? Neuroscientist 20:576–588PubMedCrossRefGoogle Scholar
  239. 239.
    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(3):e00082PubMedCentralPubMedCrossRefGoogle Scholar
  240. 240.
    Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP Jr (1985) Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol 44:559–577PubMedCrossRefGoogle Scholar
  241. 241.
    Voskuhl RR, Peterson RS, Song B, Ao Y, Morales LB, Tiwari-Woodruff S, Sofroniew MV (2009) Reactive astrocytes form scar-like perivascular barriers to leukocytes during adaptive immune inflammation of the CNS. J Neurosci 29:11511–11522PubMedCentralPubMedCrossRefGoogle Scholar
  242. 242.
    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 29:3974–3980PubMedCrossRefGoogle Scholar
  243. 243.
    Walker AK, Daniels CM, Goldman JE, Trojanowski JQ, Lee VM, Messing A (2014) Astrocytic TDP-43 pathology in Alexander disease. J Neurosci 34:6448–6458PubMedCentralPubMedCrossRefGoogle Scholar
  244. 244.
    Wallraff A, Kohling R, Heinemann U, Theis M, Willecke K, Steinhauser C (2006) The impact of astrocytic gap junctional coupling on potassium buffering in the hippocampus. J Neurosci 26:5438–5447PubMedCrossRefGoogle Scholar
  245. 245.
    Wang L, Colodner KJ, Feany MB (2011) Protein misfolding and oxidative stress promote glial-mediated neurodegeneration in an Alexander disease model. J Neurosci 31:2868–2877PubMedCentralPubMedCrossRefGoogle Scholar
  246. 246.
    Wang X, Hasan O, Arzeno A, Benowitz LI, Cafferty WB, Strittmatter SM (2012) Axonal regeneration induced by blockade of glial inhibitors coupled with activation of intrinsic neuronal growth pathways. Exp Neurol 237:55–69PubMedCentralPubMedCrossRefGoogle Scholar
  247. 247.
    Wanner IB, Anderson MA, Song B, Levine J, Fernandez A, Gray-Thompson Z, Ao Y, Sofroniew MV (2013) Glial scar borders are formed by newly proliferated, elongated astrocytes that interact to corral inflammatory and fibrotic cells via STAT3-dependent mechanisms after spinal cord injury. J Neurosci 33:12870–12886PubMedCentralPubMedCrossRefGoogle Scholar
  248. 248.
    Wharton SB, O’Callaghan JP, Savva GM, Nicoll JA, Matthews F, Simpson JE, Forster G, Shaw PJ, Brayne C, Ince PG et al (2009) Population variation in glial fibrillary acidic protein levels in brain ageing: relationship to Alzheimer-type pathology and dementia. Dement Geriatr Cogn Disord 27:465–473PubMedCrossRefGoogle Scholar
  249. 249.
    Widestrand A, Faijerson J, Wilhelmsson U, Smith PL, Li L, Sihlbom C, Eriksson PS, Pekny M (2007) Increased neurogenesis and astrogenesis from neural progenitor cells grafted in the hippocampus of GFAP−/− Vim−/− mice. Stem Cells 25:2619–2627PubMedCrossRefGoogle Scholar
  250. 250.
    Wilhelmsson U, Bushong EA, Price DL, Smarr BL, Phung V, Terada M, Ellisman MH, Pekny M (2006) Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury. Proc Natl Acad Sci 103:17513–17518PubMedCentralPubMedCrossRefGoogle Scholar
  251. 251.
    Wilhelmsson U, Faiz M, de Pablo Y, Sjoqvist M, Andersson D, Widestrand A, Potokar M, Stenovec M, Smith PL, Shinjyo N et al (2012) Astrocytes negatively regulate neurogenesis through the jagged1-mediated notch pathway. Stem Cells 30:2320–2329PubMedCrossRefGoogle Scholar
  252. 252.
    Wilhelmsson U, Li L, Pekna M, Berthold CH, Blom S, Eliasson C, Renner O, Bushong E, Ellisman M, Morgan TE et al (2004) Absence of glial fibrillary acidic protein and vimentin prevents hypertrophy of astrocytic processes and improves post-traumatic regeneration. J Neurosci 24:5016–5021PubMedCrossRefGoogle Scholar
  253. 253.
    Winter CG, Saotome Y, Levison SW, Hirsh D (1995) A role for ciliary neurotrophic factor as an inducer of reactive gliosis, the glial response to central-nervous-system injury. Proc Natl Acad Sci 92:5865–5869PubMedCentralPubMedCrossRefGoogle Scholar
  254. 254.
    Wolfe DM, Lee JH, Kumar A, Lee S, Orenstein SJ, Nixon RA (2013) Autophagy failure in Alzheimer’s disease and the role of defective lysosomal acidification. Eur J Neurosci 37:1949–1961PubMedCentralPubMedCrossRefGoogle Scholar
  255. 255.
    Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, Silverstein SC, Husemann J (2003) Adult mouse astrocytes degrade amyloid-β in vitro and in situ. Nat Med 9:453–457PubMedCrossRefGoogle Scholar
  256. 256.
    Xia XG, Hofmann HD, Deller T, Kirsch M (2002) Induction of STAT3 signaling in activated astrocytes and sprouting septal neurons following entorhinal cortex lesion in adult rats. Mol Cell Neurosci 21:379–392PubMedCrossRefGoogle Scholar
  257. 257.
    Xiao Q, Yan P, Ma X, Liu H, Perez R, Zhu A, Gonzales E, Burchett JM, Schuler DR, Cirrito JR et al (2014) Enhancing astrocytic lysosome biogenesis facilitates Aβ clearance and attenuates amyloid plaque pathogenesis. J Neurosci 34:9607–9620PubMedCentralPubMedCrossRefGoogle Scholar
  258. 258.
    Yan P, Hu X, Song H, Yin K, Bateman RJ, Cirrito JR, Xiao Q, Hsu FF, Turk JW, Xu J et al (2006) Matrix metalloproteinase-9 degrades amyloid-beta fibrils in vitro and compact plaques in situ. J Biol Chem 281:24566–24574PubMedCrossRefGoogle Scholar
  259. 259.
    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 3:271–279PubMedCrossRefGoogle Scholar
  260. 260.
    Yick LW, Wu WT, So KF, Yip HK, Shum DKY (2000) Chondroitinase ABC promotes axonal regeneration of Clarke’s neurons after spinal cord injury. NeuroReport 11:1063–1067PubMedCrossRefGoogle Scholar
  261. 261.
    Yin KJ, Cirrito JR, Yan P, Hu X, Xiao Q, Pan X, Bateman R, Song H, Hsu FF, Turk J et al (2006) Matrix metalloproteinases expressed by astrocytes mediate extracellular amyloid-beta peptide catabolism. J Neurosci 26:10939–10948PubMedCrossRefGoogle Scholar
  262. 262.
    Zamanian JL, Xu LJ, Foo LC, Nouri N, Zhou L, Giffard RG, Barres BA (2012) Genomic analysis of reactive astrogliosis. J Neurosci 32:6391–6410PubMedCentralPubMedCrossRefGoogle Scholar
  263. 263.
    Zatloukal K, Stumptner C, Fuchsbichler A, Heid H, Schnoelzer M, Kenner L, Kleinert R, Prinz M, Aguzzi A, Denk H (2002) p62 Is a common component of cytoplasmic inclusions in protein aggregation diseases. Am J Pathol 160:255–263PubMedCentralPubMedCrossRefGoogle Scholar
  264. 264.
    Zhou Y, Danbolt NC (2013) GABA and glutamate transporters in brain. Front Endocrinol 4:165CrossRefGoogle Scholar
  265. 265.
    Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57:178–201PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Milos Pekny
    • 1
    • 2
    • 3
    Email author
  • Marcela Pekna
    • 1
    • 2
    • 3
  • Albee Messing
    • 4
  • Christian Steinhäuser
    • 5
  • Jin-Moo Lee
    • 6
  • Vladimir Parpura
    • 7
  • Elly M. Hol
    • 8
    • 9
    • 10
  • Michael V. Sofroniew
    • 11
  • Alexei Verkhratsky
    • 12
    • 13
    • 14
    • 15
    Email author
  1. 1.Department of Clinical Neuroscience and RehabilitationCenter for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of GothenburgGothenburgSweden
  2. 2.Florey Institute of Neuroscience and Mental HealthParkvilleAustralia
  3. 3.University of NewcastleNew South WalesAustralia
  4. 4.Waisman CenterUniversity of Wisconsin-MadisonMadisonUSA
  5. 5.Medical faculty, Institute of Cellular NeurosciencesUniversity of BonnBonnGermany
  6. 6.Department of NeurologyThe Hope Center for Neurological Disorders, Washington University School of MedicineSt. LouisUSA
  7. 7.Department of NeurobiologyCivitan International Research Center, Center for Glial Biology in Medicine, Evelyn F. McKnight Brain Institute, Atomic Force Microscopy and Nanotechnology Laboratories, University of Alabama at BirminghamBirminghamUSA
  8. 8.Department of Translational NeuroscienceBrain Center Rudolf Magnus, University Medical Center UtrechtUtrechtThe Netherlands
  9. 9.Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Arts and SciencesAmsterdamThe Netherlands
  10. 10.Swammerdam Institute for Life Sciences, Center for NeuroscienceUniversity of AmsterdamAmsterdamThe Netherlands
  11. 11.Department of NeurobiologyUniversity of CaliforniaLos AngelesUSA
  12. 12.Faculty of Life SciencesThe University of ManchesterManchesterUK
  13. 13.Achucarro Center for Neuroscience, IKERBASQUE, Basque Foundation for ScienceBilbaoSpain
  14. 14.Department of NeurosciencesUniversity of the Basque Country UPV/EHU and CIBERNEDLeioaSpain
  15. 15.University of Nizhny NovgorodNizhny NovgorodRussia

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