Skip to main content
SpringerLink
Log in

Glial Mechanisms of Inflammation During Seizures

  • Chapter
  • First Online:
Inflammation and Epilepsy: New Vistas

Part of the book series: Progress in Inflammation Research ((PIR,volume 88))

Abstract

It is now clearly established that microglia and astrocytes become reactive in brain regions experiencing seizures in human or experimental epilepsies. The expression of these reactive phenotypes leads to the dysregulation of physiological functions normally fulfilled by these glial cells and to the acquisition of inflammatory properties that influence the activity and the fate of brain cells, including neurons, glia, and cells of the blood vessels. In this chapter, we review how dysregulation of astrocyte and microglia physiological functions and the emergence of specific reactive states impact epilepsy progression.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Abudara V, Retamal MA, Del Rio R, Orellana JA. Synaptic functions of hemichannels and pannexons: a double-edged sword. Front Mol Neurosci. 2018;11:435.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Allen NJ, Lyons DA. Glia as architects of central nervous system formation and function. Science (80- ). 2018;362:181–5.

    CAS  Google Scholar 

  3. Álvarez-Ferradas C, Morales JC, Wellmann M, Nualart F, Roncagliolo M, Fuenzalida M, Bonansco C. Enhanced astroglial Ca2+ signaling increases excitatory synaptic strength in the epileptic brain. Glia. 2015;63:1507–21.

    PubMed  Google Scholar 

  4. Alvestad S, Hammer J, Hoddevik EH, Skare Ø, Sonnewald U, Amiry-Moghaddam M, Ottersen OP. Mislocalization of AQP4 precedes chronic seizures in the kainate model of temporal lobe epilepsy. Epilepsy Res. 2013;105:30–41.

    CAS  PubMed  Google Scholar 

  5. Amhaoul H, Ali I, Mola M, Van Eetveldt A, Szewczyk K, Missault S, Bielen K, Kumar-Singh S, Rech J, Lord B, Ceusters M, Bhattacharya A, Dedeurwaerdere S. P2X7 receptor antagonism reduces the severity of spontaneous seizures in a chronic model of temporal lobe epilepsy. Neuropharmacology. 2016;105:175–85.

    CAS  PubMed  Google Scholar 

  6. Anderson MA, Ao Y, Sofroniew MV. Heterogeneity of reactive astrocytes. Neurosci Lett. 2014;565:23–9.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Andreone BJ, Lacoste B, Gu C. Neuronal and vascular interactions. Annu Rev Neurosci. 2015;38:25–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Angulo MC, Kozlov AS, Charpak S, Audinat E. Glutamate released from glial cells synchronizes neuronal activity in the hippocampus. J Neurosci. 2004;24:6920–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Angulo MC, Le Meur K, Kozlov AS, Charpak S, Audinat E. GABA, a forgotten gliotransmitter. Prog Neurobiol. 2008;86:297–303.

    CAS  PubMed  Google Scholar 

  11. Araque A, Carmignoto G, Haydon PG, Oliet SH, Robitaille R, Volterra A. Gliotransmitters travel in time and space. Neuron. 2014;81:728–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Attwell D, Buchan AM, Charpak S, Lauritzen M, Macvicar BA, Newman EA. Glial and neuronal control of brain blood flow. Nature. 2010;468:232–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Auld DS, Robitaille R. Glial cells and neurotransmission: an inclusive view of synaptic function. Neuron. 2003;40:389–400.

    CAS  PubMed  Google Scholar 

  14. Avignone E, Ulmann L, Levavasseur F, Rassendren F, Audinat E. Status epilepticus induces a particular microglial activation state characterized by enhanced purinergic signaling. J Neurosci. 2008;28:9133–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Baalman K, Marin MA, Ho TS-Y, Godoy M, Cherian L, Robertson C, Rasband MN. Axon initial segment-associated microglia. J Neurosci. 2015;35:2283–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Bauer J, Becker AJ, Elyaman W, Peltola J, Rüegg S, Titulaer MJ, Varley JA, Beghi E. Innate and adaptive immunity in human epilepsies. Epilepsia. 2017;58:57–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Bazargani N, Attwell D. Astrocyte calcium signaling: the third wave. Nat Neurosci. 2016;19:182–9.

    CAS  PubMed  Google Scholar 

  18. 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. Astrocyte uncoupling as a cause of human temporal lobe epilepsy. Brain. 2015;138:1208–22.

    PubMed  PubMed Central  Google Scholar 

  19. Beggs S, Trang T, Salter MW. P2X4R+ microglia drive neuropathic pain. Nat Neurosci. 2012;15:1068–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Benson MJ, Manzanero S, Borges K. Complex alterations in microglial M1/M2 markers during the development of epilepsy in two mouse models. Epilepsia. 2015;56:895–905.

    CAS  PubMed  Google Scholar 

  21. Bezzi P, Domercq M, Brambilla L, Galli R, Schols D, De Clercq E, Vescovi A, Bagetta G, Kollias G, Meldolesi J, Volterra A. CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity. Nat Neurosci. 2001;4:702–10.

    CAS  PubMed  Google Scholar 

  22. Biber K, Neumann H, Inoue K, Boddeke HW. Neuronal “on” and “off” signals control microglia. Trends Neurosci. 2007;30:596–602.

    CAS  PubMed  Google Scholar 

  23. Binder DK, Steinhäuser C. Functional changes in astroglial cells in epilepsy. Glia. 2006;54:358–68.

    PubMed  Google Scholar 

  24. Binder DK, Yao X, Zador Z, Sick TJ, Verkman AS, Manley GT. Increased seizure duration and slowed potassium kinetics in mice lacking aquaporin-4 water channels. Glia. 2006;53:631–6.

    PubMed  Google Scholar 

  25. Boison D. Adenosinergic signaling in epilepsy. Neuropharmacology. 2016;104:131–9.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  27. Bosco DB, Zheng J, Xu Z, Peng J, Eyo UB, Tang K, Yan C, Huang J, Feng L, Wu G, Richardson JR, Wang H, Wu LJ. RNAseq analysis of hippocampal microglia after kainic acid-induced seizures. Mol Brain. 2018;11:34.

    PubMed  PubMed Central  Google Scholar 

  28. Butt AM. ATP: a ubiquitous gliotransmitter integrating neuron–glial networks. Semin Cell Dev Biol. 2011;22:205–13.

    CAS  PubMed  Google Scholar 

  29. Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G, Dombrowski S, Dutta R, Lee JC, Cook DN, Jung S, Lira SA, Littman DR, Ransohoff RM. Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci. 2006;9:917–24.

    CAS  PubMed  Google Scholar 

  30. Cavus I, Kasoff WS, Cassaday MP, Jacob R, Gueorguieva R, Sherwin RS, Krystal JH, Spencer DD, Abi-Saab WM. Extracellular metabolites in the cortex and hippocampus of epileptic patients. Ann Neurol. 2005;57:226–35.

    CAS  PubMed  Google Scholar 

  31. Cavus I, Pan JW, Hetherington HP, Abi-Saab W, Zaveri HP, Vives KP, Krystal JH, Spencer SS, Spencer DD. Decreased hippocampal volume on MRI is associated with increased extracellular glutamate in epilepsy patients. Epilepsia. 2008;49:1358–66.

    PubMed  Google Scholar 

  32. Chever O, Djukic B, McCarthy KD, Amzica F. Implication of Kir4.1 channel in excess potassium clearance: an in vivo study on anesthetized glial-conditional Kir4.1 knock-out mice. J Neurosci. 2010;30:15769–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Choi DW. Glutamate neurotoxicity and diseases of the nervous system. Neuron. 1988;1:623–34.

    CAS  PubMed  Google Scholar 

  34. Choo AM, Miller WJ, Chen Y-C, Nibley P, Patel TP, Goletiani C, Morrison B, Kutzing MK, Firestein BL, Sul J-Y, Haydon PG, Meaney DF. Antagonism of purinergic signalling improves recovery from traumatic brain injury. Brain. 2013;136:65–80.

    PubMed  PubMed Central  Google Scholar 

  35. Clasadonte J, Dong J, Hines DJ, Haydon PG. Astrocyte control of synaptic NMDA receptors contributes to the progressive development of temporal lobe epilepsy. Proc Natl Acad Sci U S A. 2013;110:17540–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Cope DW, Di GG, Fyson SJ, Orban G, Errington AC, Lorincz ML, Gould TM, Carter DA, Crunelli V. Enhanced tonic GABAA inhibition in typical absence epilepsy. Nat Med. 2009;15:1392–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Coulter DA, Eid T. Astrocytic regulation of glutamate homeostasis in epilepsy. Glia. 2012;60:1215–26.

    PubMed  PubMed Central  Google Scholar 

  38. Cresto N, Pillet L-E, Billuart P, Rouach N. Do astrocytes play a role in intellectual disabilities? Trends Neurosci. 2019;42:518–27.

    CAS  PubMed  Google Scholar 

  39. Cserép C, et al. Microglia monitor and protect neuronal function through specialized somatic purinergic junctions. Science (80- ). 2020;367:528–37.

    Google Scholar 

  40. Cunha RA. How does adenosine control neuronal dysfunction and neurodegeneration? J Neurochem. 2016;139:1019–55.

    CAS  PubMed  Google Scholar 

  41. D’Ambrosio R, Gordon DS, Winn HR. Differential role of KIR channel and Na(+)/K(+)-pump in the regulation of extracellular K(+) in rat hippocampus. J Neurophysiol. 2002;87:87–102.

    PubMed  Google Scholar 

  42. Dallérac G, Rouach N. Astrocytes as new targets to improve cognitive functions. Prog Neurobiol. 2016;144:48–67.

    PubMed  Google Scholar 

  43. Dallérac G, Zapata J, Rouach N. Versatile control of synaptic circuits by astrocytes: where, when and how? Nat Rev Neurosci. 2018;19:729–43.

    PubMed  Google Scholar 

  44. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci. 2005;8:752–8.

    CAS  PubMed  Google Scholar 

  45. De Biase LM, Schuebel KE, Fusfeld ZH, Jair K, Hawes IA, Cimbro R, Zhang HY, Liu QR, Shen H, Xi ZX, Goldman D, Bonci A. Local cues establish and maintain region-specific phenotypes of basal ganglia microglia. Neuron. 2017;95:341–356.e6.

    PubMed  PubMed Central  Google Scholar 

  46. Delekate A, Füchtemeier M, Schumacher T, Ulbrich C, Foddis M, Petzold GC. Metabotropic P2Y1 receptor signalling mediates astrocytic hyperactivity in vivo in an Alzheimer’s disease mouse model. Nat Commun. 2014;5:5422.

    PubMed  Google Scholar 

  47. Ding S, Fellin T, Zhu Y, Lee SY, Auberson YP, Meaney DF, Coulter DA, Carmignoto G, Haydon PG. Enhanced astrocytic Ca2+ signals contribute to neuronal excitotoxicity after status epilepticus. J Neurosci. 2007;27:10674–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Dissing-Olesen L, LeDue JM, Rungta RL, Hefendehl JK, Choi HB, MacVicar BA. Activation of neuronal NMDA receptors triggers transient ATP-mediated microglial process outgrowth. J Neurosci. 2014;34:10511–27.

    PubMed  PubMed Central  Google Scholar 

  49. Djukic B, Casper KB, Philpot BD, Chin LS, McCarthy KD. 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. 2007;27:11354–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Dossi E, Blauwblomme T, Moulard J, Chever O, Vasile F, Guinard E, Le Bert M, Couillin I, Pallud J, Capelle L, Huberfeld G, Rouach N. Pannexin-1 channels contribute to seizure generation in human epileptic brain tissue and in a mouse model of epilepsy. Sci Transl Med. 2018a;10:eaar3796.

    PubMed  Google Scholar 

  51. Dossi E, Vasile F, Rouach N. Human astrocytes in the diseased brain. Brain Res Bull. 2018b;136:139–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. During MJ, Spencer DD. Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet. 1993;341:1607–10. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8099987

    CAS  PubMed  Google Scholar 

  53. Eid T, Ghosh A, Wang Y, Beckstrom H, Zaveri HP, Lee T-SW, Lai JCK, Malthankar-Phatak GH, de Lanerolle NC. Recurrent seizures and brain pathology after inhibition of glutamine synthetase in the hippocampus in rats. Brain. 2008;131:2061–70.

    PubMed  PubMed Central  Google Scholar 

  54. Eid T, Gruenbaum SE, Dhaher R, Lee T-SW, Zhou Y, Danbolt NC. The glutamate–glutamine cycle in epilepsy. In: Advances in neurobiology. New York: Springer; 2016. p. 351–400.

    Google Scholar 

  55. Eid T, Lee T-SW, Thomas MJ, Amiry-Moghaddam M, Bjørnsen LP, Spencer DD, Agre P, Ottersen OP, de Lanerolle NC. Loss of perivascular aquaporin 4 may underlie deficient water and K+ homeostasis in the human epileptogenic hippocampus. Proc Natl Acad Sci U S A. 2005;102:1193–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Eid T, Thomas MJ, Spencer DD, Rundén-Pran E, Lai JCK, Malthankar GV, Kim JH, Danbolt NC, Ottersen OP, de Lanerolle NC. Loss of glutamine synthetase in the human epileptogenic hippocampus: possible mechanism for raised extracellular glutamate in mesial temporal lobe epilepsy. Lancet (London, England). 2004;363:28–37.

    CAS  PubMed  Google Scholar 

  57. Elmore MR, Najafi AR, Koike MA, Dagher NN, Spangenberg EE, Rice RA, Kitazawa M, Matusow B, Nguyen H, West BL, Green KN. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron. 2014;82:380–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Etherington L-AV, Patterson GE, Meechan L, Boison D, Irving AJ, Dale N, Frenguelli BG. Astrocytic adenosine kinase regulates basal synaptic adenosine levels and seizure activity but not activity-dependent adenosine release in the hippocampus. Neuropharmacology. 2009;56:429–37.

    CAS  PubMed  Google Scholar 

  59. Eyo UB, Peng J, Murugan M, Mo M, Lalani A, Xie P, Xu P, Margolis DJ, Wu LJ. Regulation of physical microglia–neuron interactions by fractalkine signaling after status epilepticus. eNeuro. 2016;3:e0209.

    Google Scholar 

  60. Eyo UB, Peng JY, Swiatkowski P, Mukherjee A, Bispo A, Wu LJ. Neuronal hyperactivity recruits microglial processes via neuronal NMDA receptors and microglial P2Y12 receptors after status epilepticus. J Neurosci. 2014;34:10528–40.

    PubMed  PubMed Central  Google Scholar 

  61. Fabene PF, et al. A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nat Med. 2008;14:1377–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Fellin T, Gomez-Gonzalo M, Gobbo S, Carmignoto G, Haydon PG. Astrocytic glutamate is not necessary for the generation of epileptiform neuronal activity in hippocampal slices. J Neurosci. 2006;26:9312–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Fellin T, Pascual O, Gobbo S, Pozzan T, Haydon PG, Carmignoto G. Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron. 2004;43:729–43.

    CAS  PubMed  Google Scholar 

  64. Fiacco TA, McCarthy KD. Multiple lines of evidence indicate that gliotransmission does not occur under physiological conditions. J Neurosci. 2018;38:3–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Giaume C, Koulakoff A, Roux L, Holcman D, Rouach N. Astroglial networks: a step further in neuroglial and gliovascular interactions. Nat Rev Neurosci. 2010;11:87–99.

    CAS  PubMed  Google Scholar 

  66. Gomez-Gonzalo M, et al. An excitatory loop with astrocytes contributes to drive neurons to seizure threshold. PLoS Biol. 2010;8:e1000352.

    PubMed  PubMed Central  Google Scholar 

  67. Gorter JA, Van Vliet EA, Aronica E. Status epilepticus, blood-brain barrier disruption, inflammation, and epileptogenesis. Epilepsy Behav. 2015;49:13–6.

    PubMed  Google Scholar 

  68. Gross A, Benninger F, Madar R, Illouz T, Griffioen K, Steiner I, Offen D, Okun E. Toll-like receptor 3 deficiency decreases epileptogenesis in a pilocarpine model of SE-induced epilepsy in mice. Epilepsia. 2017;58:586–96.

    CAS  PubMed  Google Scholar 

  69. Halassa MM, Fellin T, Haydon PG. The tripartite synapse: roles for gliotransmission in health and disease. Trends Mol Med. 2007;13:54–63.

    CAS  PubMed  Google Scholar 

  70. Hamilton NB, Attwell D. Do astrocytes really exocytose neurotransmitters? Nat Rev Neurosci. 2010;11:227–38.

    CAS  PubMed  Google Scholar 

  71. Hanisch UK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 2007;10:1387–94.

    CAS  PubMed  Google Scholar 

  72. Harada K, Kamiya T, Tsuboi T. Gliotransmitter release from astrocytes: functional, developmental, and pathological implications in the brain. Front Neurosci. 2016;9:499.

    PubMed  PubMed Central  Google Scholar 

  73. Haynes SE, Hollopeter G, Yang G, Kurpius D, Dailey ME, Gan WB, Julius D. The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci. 2006;9:1512–9.

    CAS  PubMed  Google Scholar 

  74. Heinemann U, Dieter Lux H. Ceiling of stimulus induced rises in extracellular potassium concentration in the cerebral cortex of cat. Brain Res. 1977;120:231–49.

    CAS  PubMed  Google Scholar 

  75. Heinemann U, Gabriel S, Jauch R, Schulze K, Kivi A, Eilers A, Kovacs R, Lehmann TN. Alterations of glial cell function in temporal lobe epilepsy. Epilepsia. 2000;41(Suppl 6):S185–9.

    PubMed  Google Scholar 

  76. Heinemann U, Kaufer D, Friedman A. Blood-brain barrier dysfunction, TGFbeta signaling, and astrocyte dysfunction in epilepsy. Glia. 2012;60:1251–7.

    PubMed  PubMed Central  Google Scholar 

  77. Heuser K, Eid T, Lauritzen F, Thoren AE, Vindedal GF, Taubøll E, Gjerstad L, Spencer DD, Ottersen OP, Nagelhus EA, Lanerolle NC de. Loss of perivascular Kir4.1 potassium channels in the sclerotic hippocampus of patients with mesial temporal lobe epilepsy. J Neuropathol Exp Neurol. 2012;71:814–25.

    CAS  PubMed  Google Scholar 

  78. Heuser K, Nome CG, Pettersen KH, Åbjørsbråten KS, Jensen V, Tang W, Sprengel R, Taubøll E, Nagelhus EA, Enger R. Ca2+ signals in astrocytes facilitate spread of epileptiform activity. Cereb Cortex. 2018;28:4036–48.

    PubMed  PubMed Central  Google Scholar 

  79. Hinterkeuser S, Schröder W, Hager G, Seifert G, Blümcke I, Elger CE, Schramm J, Steinhäuser C. Astrocytes in the hippocampus of patients with temporal lobe epilepsy display changes in potassium conductances. Eur J Neurosci. 2000;12:2087–96.

    CAS  PubMed  Google Scholar 

  80. Hirbec H, Marmai C, Duroux-Richard I, Roubert C, Esclangon A, Croze S, Lachuer J, Peyroutou R, Rassendren F. The microglial reaction signature revealed by RNAseq from individual mice. Glia. 2018;66(5):971–86.

    PubMed  Google Scholar 

  81. Hirbec H, Rassendren F, Audinat E. Microglia reactivity: heterogeneous pathological phenotypes. Methods Mol Biol. 2019;2034:41–55.

    CAS  PubMed  Google Scholar 

  82. Inoue K, Tsuda M. Purinergic systems, neuropathic pain and the role of microglia. Exp Neurol. 2012;234:293–301.

    CAS  PubMed  Google Scholar 

  83. Ising C, Heneka MT. Functional and structural damage of neurons by innate immune mechanisms during neurodegeneration review-article. Cell Death Dis. 2018;9(2):120.

    PubMed  PubMed Central  Google Scholar 

  84. Iyer A, Zurolo E, Prabowo A, Fluiter K, Spliet WGM, van Rijen PC, Gorter JA, Aronica E. MicroRNA-146a: a key regulator of astrocyte-mediated inflammatory response. PLoS One. 2012;7:e44789.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Jauch R, Windmüller O, Lehmann T-N, Heinemann U, Gabriel S. Effects of barium, furosemide, ouabaine and 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS) on ionophoretically-induced changes in extracellular potassium concentration in hippocampal slices from rats and from patients with epilepsy. Brain Res. 2002;925:18–27.

    CAS  PubMed  Google Scholar 

  86. Jimenez-Mateos EM, et al. microRNA targeting of the P2X7 purinoceptor opposes a contralateral epileptogenic focus in the hippocampus. Sci Rep. 2015;5:17486.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Kato G, Inada H, Wake H, Akiyoshi R, Miyamoto A, Eto K, Ishikawa T, Moorhouse AJ, Strassman AM, Nabekura J. Microglial contact prevents excess depolarization and rescues neurons from excitotoxicity. eNeuro. 2016;3:9133–44.

    Google Scholar 

  88. Kettenmann H, Kirchhoff F, Verkhratsky A. Microglia: new roles for the synaptic stripper. Neuron. 2013;77:10–8.

    CAS  PubMed  Google Scholar 

  89. Keystone EC, Wang MM, Layton M, Hollis S, McInnes IB. Clinical evaluation of the efficacy of the P2X7 purinergic receptor antagonist AZD9056 on the signs and symptoms of rheumatoid arthritis in patients with active disease despite treatment with methotrexate or sulphasalazine. Ann Rheum Dis. 2012;71:1630–5.

    CAS  PubMed  Google Scholar 

  90. Khakh BS, Gittermann D, Cockayne DA, Jones A. ATP modulation of excitatory synapses onto interneurons. J Neurosci. 2003;23:7426–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Khakh BS, Sofroniew MV. Diversity of astrocyte functions and phenotypes in neural circuits. Nat Neurosci. 2015;18:942–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Kierdorf K, Prinz M. Factors regulating microglia activation. Front Cell Neurosci. 2013;7:44.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Kim JE, Kang TC. The P2X7 receptor-pannexin-1 complex decreases muscarinic acetylcholine receptor-mediated seizure susceptibility in mice. J Clin Invest. 2011;121:2037–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Kim JE, Ryu HJ, Kang TC. Status epilepticus induces vasogenic edema via tumor necrosis factor-α/ endothelin-1-mediated two different pathways. PLoS One. 2013;8:e74458.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Kim SY, Senatorov VV, Morrissey CS, Lippmann K, Vazquez O, Milikovsky DZ, Gu F, Parada I, Prince DA, Becker AJ, Heinemann U, Friedman A, Kaufer D. TGFβ signaling is associated with changes in inflammatory gene expression and perineuronal net degradation around inhibitory neurons following various neurological insults. Sci Rep. 2017;7:7711.

    PubMed  PubMed Central  Google Scholar 

  96. Kivi A, Lehmann TN, Kovacs R, Eilers A, Jauch R, Meencke HJ, von DA, Heinemann U, Gabriel S. Effects of barium on stimulus-induced rises of [K+]o in human epileptic non-sclerotic and sclerotic hippocampal area CA1. Eur J Neurosci. 2000;12:2039–48.

    CAS  PubMed  Google Scholar 

  97. Klement W, Blaquiere M, Zub E, deBock F, Boux F, Barbier E, Audinat E, Lerner-Natoli M, Marchi N. A pericyte-glia scarring develops at the leaky capillaries in the hippocampus during seizure activity. Epilepsia. 2019;60:1399–411.

    CAS  PubMed  Google Scholar 

  98. Klement W, Garbelli R, Zub E, Rossini L, Tassi L, Girard B, Blaquiere M, Bertaso F, Perroy J, de Bock F, Marchi N. Seizure progression and inflammatory mediators promote pericytosis and pericyte-microglia clustering at the cerebrovasculature. Neurobiol Dis. 2018;113:70–81.

    CAS  PubMed  Google Scholar 

  99. Kofuji P, Newman EA. Potassium buffering in the central nervous system. Neuroscience. 2004;129:1043–54.

    Google Scholar 

  100. Korotkov A, Broekaart DWM, Banchaewa L, Pustjens B, van Scheppingen J, Anink JJ, Baayen JC, Idema S, Gorter JA, van Vliet EA, Aronica E. microRNA-132 is overexpressed in glia in temporal lobe epilepsy and reduces the expression of pro-epileptogenic factors in human cultured astrocytes. Glia. 2020;68:60–75.

    PubMed  Google Scholar 

  101. Lado FA, Moshé SL. How do seizures stop? Epilepsia. 2008;49:1651–64.

    PubMed  PubMed Central  Google Scholar 

  102. Lee T-S, Bjørnsen LP, Paz C, Kim JH, Spencer SS, Spencer DD, Eid T, de Lanerolle NC. GAT1 and GAT3 expression are differently localized in the human epileptogenic hippocampus. Acta Neuropathol. 2006;111:351–63.

    CAS  PubMed  Google Scholar 

  103. Li Y, Du XF, Liu CS, Wen ZL, Du JL. Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo. Dev Cell. 2012;23:1189–202.

    CAS  PubMed  Google Scholar 

  104. Lian H, Yang L, Cole A, Sun L, Chiang AC-A, Fowler SW, Shim DJ, Rodriguez-Rivera J, Taglialatela G, Jankowsky JL, Lu H-C, Zheng H. NFκB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer’s disease. Neuron. 2015;85:101–15.

    CAS  PubMed  Google Scholar 

  105. Liddelow SA, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541:481–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Liddelow SA, Barres BA. Reactive astrocytes: production, function, and therapeutic potential. Immunity. 2017;46:957–67.

    CAS  PubMed  Google Scholar 

  107. Limatola C, Ransohoff RM. Modulating neurotoxicity through CX3CL1/CX3CR1 signaling. Front Cell Neurosci. 2014;8:229.

    PubMed  PubMed Central  Google Scholar 

  108. Madry C, Kyrargyri V, Arancibia-Cárcamo IL, Jolivet R, Kohsaka S, Bryan RM, Attwell D. Microglial ramification, surveillance, and interleukin-1β release are regulated by the two-pore domain K+channel THIK-1. Neuron. 2018;97(2):299–312.e6.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Malarkey EB, Parpura V. Mechanisms of glutamate release from astrocytes. Neurochem Int. 2008;52:142–54.

    CAS  PubMed  Google Scholar 

  110. Marchi N, Granata T, Janigro D. Inflammatory pathways of seizure disorders. Trends Neurosci. 2014;37:55–65.

    CAS  PubMed  Google Scholar 

  111. Maroso M, Balosso S, Ravizza T, Liu J, Aronica E, Iyer AM, Rossetti C, Molteni M, Casalgrandi M, Manfredi AA, Bianchi ME, Vezzani A. Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nat Med. 2010;16:413–9.

    CAS  PubMed  Google Scholar 

  112. Meldrum BS. The role of glutamate in epilepsy and other CNS disorders. Neurology. 1994;44:S14–23.

    CAS  PubMed  Google Scholar 

  113. Meme W, Calvo C-FF, Froger N, Ezan P, Amigou E, Koulakoff A, Giaume C, Même W, Calvo C-FF, Froger N, Ezan P, Amigou E, Koulakoff A, Giaume C. Proinflammatory cytokines released from microglia inhibit gap junctions in astrocytes: potentiation by beta-amyloid. FASEB J. 2006;20:494–6.

    CAS  PubMed  Google Scholar 

  114. Messing A, Brenner M, Feany MB, Nedergaard M, Goldman JE. Alexander disease. J Neurosci. 2012;32:5017–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Milior G, Morin-Brureau M, Chali F, Le Duigou C, Savary E, Huberfeld G, Rouach N, Pallud J, Capelle L, Navarro V, Mathon B, Clemenceau S, Miles R. Distinct P2Y receptors mediate extension and retraction of microglial processes in epileptic and peritumoral human tissue. J Neurosci. 2020;40:1373–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Mo M, Eyo UB, Xie M, Peng J, Bosco DB, Umpierre AD, Zhu X, Tian DS, Xu P, Wu LJ. Microglial P2Y12 receptor regulates seizure-induced neurogenesis and immature neuronal projections. J Neurosci. 2019;39:9453–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Morin-Brureau M, Milior G, Royer J, Chali F, Le Duigou C, Savary E, Blugeon C, Jourdren L, Akbar D, Dupont S, Navarro V, Baulac M, Bielle F, Mathon B, Clemenceau S, Miles R. Microglial phenotypes in the human epileptic temporal lobe. Brain. 2018;141(12):3343–60.

    PubMed  Google Scholar 

  118. Mosser CA, Baptista S, Arnoux I, Audinat E. Microglia in CNS development: shaping the brain for the future. Prog Neurobiol. 2017;149–150:1–20.

    PubMed  Google Scholar 

  119. Nagy JI, Rash JE. Connexins and gap junctions of astrocytes and oligodendrocytes in the CNS. Brain Res Brain Res Rev. 2000;32:29–44.

    CAS  PubMed  Google Scholar 

  120. Nayak D, Roth TL, McGavern DB. Microglia development and function. Annu Rev Immunol. 2014;32:367–402.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Nikolic L, Shen W, Nobili P, Virenque A, Ulmann L, Audinat E. Blocking TNFα-driven astrocyte purinergic signaling restores normal synaptic activity during epileptogenesis. Glia. 2018;66:2673–83.

    PubMed  Google Scholar 

  122. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science (80- ). 2005;308:1314–8.

    CAS  Google Scholar 

  123. Nippert AR, Biesecker KR, Newman EA. Mechanisms mediating functional hyperemia in the brain. Neuroscientist. 2018;24:73–83.

    CAS  PubMed  Google Scholar 

  124. Noè F, Cattalini A, Vila Verde D, Alessi C, Colciaghi F, Figini M, Zucca I, Curtis M. Epileptiform activity contralateral to unilateral hippocampal sclerosis does not cause the expression of brain damage markers. Epilepsia. 2019;60:epi.15611.

    Google Scholar 

  125. Nortley R, Attwell D. Control of brain energy supply by astrocytes. Curr Opin Neurobiol. 2017;47:80–5.

    CAS  PubMed  Google Scholar 

  126. Olson JK, Miller SD. Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol. 2004;173:3916–24.

    CAS  PubMed  Google Scholar 

  127. Orkand RK, Nicholls JG, Kuffler SW. Effect of nerve impulses on the membrane potential of glial cells in the central nervous system of amphibia. J Neurophysiol. 1966;29:788–806.

    CAS  PubMed  Google Scholar 

  128. Orr AG, Orr AL, Li XJ, Gross RE, Traynelis SF. Adenosine A(2A) receptor mediates microglial process retraction. Nat Neurosci. 2009;12:872–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Ortinski PI, Dong J, Mungenast A, Yue C, Takano H, Watson DJ, Haydon PG, Coulter DA. Selective induction of astrocytic gliosis generates deficits in neuronal inhibition. Nat Neurosci. 2010;13:584–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Panatier A, Robitaille R. Astrocytic mGluR5 and the tripartite synapse. Neuroscience. 2016;323:29–34.

    CAS  PubMed  Google Scholar 

  131. Pannasch U, Vargova L, Reingruber J, Ezan P, Holcman D, Giaume C, Sykova E, Rouach N. Astroglial networks scale synaptic activity and plasticity. Proc Natl Acad Sci U S A. 2011;108:8467–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Paolicelli RC, Ferretti MT. Function and dysfunction of microglia during brain development: consequences for synapses and neural circuits. Front Synaptic Neurosci. 2017;9:9.

    PubMed  PubMed Central  Google Scholar 

  133. Papadopoulos MC, Verkman AS. Aquaporin water channels in the nervous system. Nat Rev Neurosci. 2013;14:265–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Papouin T, Dunphy J, Tolman M, Foley JC, Haydon PG. Astrocytic control of synaptic function. Philos Trans R Soc B Biol Sci. 2017;372:20160154.

    Google Scholar 

  135. Parkhurst CN, Yang G, Ninan I, Savas JN, Yates JR III, Lafaille JJ, Hempstead BL, Littman DR, Gan WB. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell. 2013;155:1596–609.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Parri HR, Gould TM, Crunelli V. Spontaneous astrocytic Ca2+ oscillations in situ drive NMDAR-mediated neuronal excitation. Nat Neurosci. 2001;4:803–12.

    CAS  PubMed  Google Scholar 

  137. Pascual O, Ben Achour S, Rostaing P, Triller A, Bessis A. Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission. Proc Natl Acad Sci. 2012;109:E197–205.

    CAS  PubMed  Google Scholar 

  138. Pascual O, Casper KB, Kubera C, Zhang J, Revilla-Sanchez R, Sul J-YY, Takano H, Moss SJ, McCarthy K, Haydon PG. Astrocytic purinergic signaling coordinates synaptic networks. Science (80- ). 2005;310:113–6.

    CAS  Google Scholar 

  139. Patel DC, Tewari BP, Chaunsali L, Sontheimer H. Neuron–glia interactions in the pathophysiology of epilepsy. Nat Rev Neurosci. 2019;20:282–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Pellerin L, Bouzier-Sore A-K, Aubert A, Serres S, Merle M, Costalat R, Magistretti PJ. Activity-dependent regulation of energy metabolism by astrocytes: an update. Glia. 2007;55:1251–62.

    PubMed  Google Scholar 

  141. Pellerin L, Magistretti PJ. Sweet sixteen for ANLS. J Cereb Blood Flow Metab. 2012;32:1152–66.

    CAS  PubMed  Google Scholar 

  142. Perea G, Navarrete M, Araque A. Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci. 2009;32:421–31.

    CAS  PubMed  Google Scholar 

  143. Petrelli F, Bezzi P. Novel insights into gliotransmitters. Curr Opin Pharmacol. 2016;26:138–45.

    CAS  PubMed  Google Scholar 

  144. Pfeiffer T, Avignone E, Nägerl UV. Induction of hippocampal long-term potentiation increases the morphological dynamics of microglial processes and prolongs their contacts with dendritic spines. Sci Rep. 2016;6:32422.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Pirttimaki T, Parri HR, Crunelli V. Astrocytic GABA transporter GAT-1 dysfunction in experimental absence seizures. J Physiol. 2013;591:823–33.

    CAS  PubMed  Google Scholar 

  146. Prinz M, Priller J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci. 2014;15:300–12.

    CAS  PubMed  Google Scholar 

  147. Ransohoff RM, Perry VH. Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol. 2009;27:119–45.

    CAS  PubMed  Google Scholar 

  148. Ransom CB, Ransom BR, Sontheimer H. Activity-dependent extracellular K+ accumulation in rat optic nerve: the role of glial and axonal Na+ pumps. J Physiol. 2000;522(Pt 3):427–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Reichenbach N, Delekate A, Breithausen B, Keppler K, Poll S, Schulte T, Peter J, Plescher M, Hansen JN, Blank N, Keller A, Fuhrmann M, Henneberger C, Halle A, Petzold GC. P2Y1 receptor blockade normalizes network dysfunction and cognition in an Alzheimer’s disease model. J Exp Med. 2018;215:1649–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Robel S, Buckingham SC, Boni JL, Campbell SL, Danbolt NC, Riedemann T, Sutor B, Sontheimer H. Reactive astrogliosis causes the development of spontaneous seizures. J Neurosci. 2015;35:3330–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Rodrigues RJ, Tome AR, Cunha RA. ATP as a multi-target danger signal in the brain. Front Neurosci. 2015;9:148.

    PubMed  PubMed Central  Google Scholar 

  152. Rogers JT, Morganti JM, Bachstetter AD, Hudson CE, Peters MM, Grimmig BA, Weeber EJ, Bickford PC, Gemma C. CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity. J Neurosci. 2011;31:16241–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Roseti C, Fucile S, Lauro C, Martinello K, Bertollini C, Esposito V, Mascia A, Catalano M, Aronica E, Limatola C, Palma E. Fractalkine/CX3CL1 modulates GABAA currents in human temporal lobe epilepsy. Epilepsia. 2013;54:1834–44.

    CAS  PubMed  Google Scholar 

  154. Rossi D, Volterra A. Astrocytic dysfunction: insights on the role in neurodegeneration. Brain Res Bull. 2009;80:224–32.

    CAS  PubMed  Google Scholar 

  155. Rossini L, Garbelli R, Gnatkovsky V, Didato G, Villani F, Spreafico R, Deleo F, Lo Russo G, Tringali G, Gozzo F, Tassi L, de Curtis M. Seizure activity per se does not induce tissue damage markers in human neocortical focal epilepsy. Ann Neurol. 2017;82:331–41.

    CAS  PubMed  Google Scholar 

  156. Rusakov DA, Bard L, Stewart MG, Henneberger C. Diversity of astroglial functions alludes to subcellular specialisation. Trends Neurosci. 2014;37:228–42.

    CAS  PubMed  Google Scholar 

  157. Salter MW, Beggs S. Sublime microglia: expanding roles for the guardians of the CNS. Cell. 2014;158:15–24.

    CAS  PubMed  Google Scholar 

  158. Salter MW, Stevens B. Microglia emerge as central players in brain disease. Nat Med. 2017;23(9):1018–27.

    CAS  PubMed  Google Scholar 

  159. Sanchez JMS, DePaula-Silva AB, Doty DJ, Truong A, Libbey JE, Fujinami RS. Microglial cell depletion is fatal with low level picornavirus infection of the central nervous system. J Neurovirol. 2019;25:415–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Santello M, Toni N, Volterra A. Astrocyte function from information processing to cognition and cognitive impairment. Nat Neurosci. 2019;22:154–66.

    CAS  PubMed  Google Scholar 

  161. Santiago MF, Veliskova J, Patel NK, Lutz SE, Caille D, Charollais A, Meda P, Scemes E. Targeting pannexin1 improves seizure outcome Barnes S. PLoS One. 2011;6:e25178.

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Savtchouk I, Volterra A. Gliotransmission: beyond black-and-white. J Neurosci. 2018;38:14–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Schafer DP, Lehrman EK, Stevens B. The “quad-partite” synapse: microglia-synapse interactions in the developing and mature CNS. Glia. 2013;61:24–36.

    PubMed  Google Scholar 

  164. Schröder W, Hinterkeuser S, Seifert G, Schramm J, Jabs R, Wilkin GP, Steinhäuser C, Schroder W, Hinterkeuser S, Seifert G, Schramm J, Jabs R, Wilkin GP, Steinhauser C. Functional and molecular properties of human astrocytes in acute hippocampal slices obtained from patients with temporal lobe epilepsy. Epilepsia. 2000;41(Suppl 6):S181–4.

    PubMed  Google Scholar 

  165. Schwartzkroin PA, Baraban SC, Hochman DW. Osmolarity, ionic flux, and changes in brain excitability. Epilepsy Res. 1998;32:275–85.

    CAS  PubMed  Google Scholar 

  166. Scianni M, Antonilli L, Chece G, Cristalli G, Di Castro MA, Limatola C, Maggi L. Fractalkine (CX3CL1) enhances hippocampal N-methyl-D-aspartate receptor (NMDAR) function via D-serine and adenosine receptor type A2 (A2AR) activity. J Neuroinflammation. 2013;10:108.

    PubMed  PubMed Central  Google Scholar 

  167. Seifert G, Hüttmann K, Binder DK, Hartmann C, Wyczynski A, Neusch C, Steinhäuser C. Analysis of astroglial K+ channel expression in the developing hippocampus reveals a predominant role of the Kir4.1 subunit. J Neurosci. 2009;29:7474–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Seiffert E, Dreier JP, Ivens S, Bechmann I, Tomkins O, Heinemann U, Friedman A. Lasting blood-brain barrier disruption induces epileptic focus in the rat somatosensory cortex. J Neurosci. 2004;24:7829–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Shemer A, Erny D, Jung S, Prinz M. Microglia plasticity during health and disease: an immunological perspective. Trends Immunol. 2015;36:614–24.

    CAS  PubMed  Google Scholar 

  170. Shen W, Nikolic L, Meunier C, Pfrieger F, Audinat E. An autocrine purinergic signaling controls astrocyte-induced neuronal excitation. Sci Rep. 2017;7:11280.

    PubMed  PubMed Central  Google Scholar 

  171. Sierra A, Encinas JM, Deudero JJ, Chancey JH, Enikolopov G, Overstreet-Wadiche LS, Tsirka SE, Maletic-Savatic M. Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell. 2010;7:483–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Sipe GO, Lowery RL, Tremblay ME, Kelly EA, Lamantia CE, Majewska AK. Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex. Nat Commun. 2016;7:10905.

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Sofroniew MV. Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci. 2009;32:638–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Song C, Xu W, Zhang X, Wang S, Zhu G, Xiao T, Zhao M, Zhao C. CXCR4 antagonist AMD3100 suppresses the long-term abnormal structural changes of newborn neurons in the intraventricular kainic acid model of epilepsy. Mol Neurobiol. 2016;53:1518–32.

    CAS  PubMed  Google Scholar 

  175. Srivastava PK, et al. A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target. Nat Commun. 2018;9:3561.

    PubMed  PubMed Central  Google Scholar 

  176. Steinhäuser C, Grunnet M, Carmignoto G. Crucial role of astrocytes in temporal lobe epilepsy. Neuroscience. 2016;323:157–69.

    PubMed  Google Scholar 

  177. Stowell RD, Wong EL, Batchelor HN, Mendes MS, Lamantia CE, Whitelaw BS, Majewska AK. Cerebellar microglia are dynamically unique and survey Purkinje neurons in vivo. Dev Neurobiol. 2018;78:627–44.

    PubMed  PubMed Central  Google Scholar 

  178. Strohschein S, Hüttmann K, Gabriel S, Binder DK, Heinemann U, Steinhäuser C. Impact of aquaporin-4 channels on K+ buffering and gap junction coupling in the hippocampus. Glia. 2011;59:973–80.

    PubMed  Google Scholar 

  179. Studer FE, Fedele DE, Marowsky A, Schwerdel C, Wernli K, Vogt K, Fritschy JM, Boison D. Shift of adenosine kinase expression from neurons to astrocytes during postnatal development suggests dual functionality of the enzyme. Neuroscience. 2006;142:125–37.

    CAS  PubMed  Google Scholar 

  180. Szokol K, Heuser K, Tang W, Jensen V, Enger R, Bedner P, Steinhauser C, Tauboll E, Ottersen OP, Nagelhus EA. Augmentation of Ca(2+) signaling in astrocytic endfeet in the latent phase of temporal lobe epilepsy. Front Cell Neurosci 2015;9:49.

    Google Scholar 

  181. Tan Z, Liu Y, Xi W, Lou H, Zhu L, Guo Z, Mei L, Duan S. Glia-derived ATP inversely regulates excitability of pyramidal and CCK-positive neurons. Nat Commun. 2017;8:13772.

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 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. Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science (80- ). 1997;276:1699–702.

    CAS  Google Scholar 

  183. Terrone G, Balosso S, Pauletti A, Ravizza T, Vezzani A. Inflammation and reactive oxygen species as disease modifiers in epilepsy. Neuropharmacology. 2019;167:107742.

    PubMed  Google Scholar 

  184. Terrone G, Salamone A, Vezzani A. Inflammation and epilepsy: preclinical findings and potential clinical translation. Curr Pharm Des. 2017;23:5569–76.

    CAS  PubMed  Google Scholar 

  185. Theodosis DT, Poulain DA, Oliet SHR. Activity-dependent structural and functional plasticity of astrocyte-neuron interactions. Physiol Rev. 2008;88:983–1008.

    CAS  PubMed  Google Scholar 

  186. Thion MS, Ginhoux F, Garel S. Microglia and early brain development: an intimate journey. Science. 2018;362:185–9.

    CAS  PubMed  Google Scholar 

  187. Thom M. Review: hippocampal sclerosis in epilepsy: a neuropathology review. Neuropathol Appl Neurobiol. 2014;40:520–43.

    PubMed  PubMed Central  Google Scholar 

  188. Tian GF, Azmi H, Takano T, Xu Q, Peng W, Lin J, Oberheim N, Lou N, Wang X, Zielke HR, Kang J, Nedergaard M. An astrocytic basis of epilepsy. Nat Med. 2005;11:973–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Tozaki-Saitoh H, Tsuda M, Miyata H, Ueda K, Kohsaka S, Inoue K. P2Y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury. J Neurosci. 2008;28:4949–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Tremblay ME, Lowery RL, Majewska AK. Microglial interactions with synapses are modulated by visual experience. PLoS Biol. 2010;8:e1000527.

    PubMed  PubMed Central  Google Scholar 

  191. Tremblay ME, Stevens B, Sierra A, Wake H, Bessis A, Nimmerjahn A. The role of microglia in the healthy brain. J Neurosci. 2011;31:16064–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Ulmann L, Levavasseur F, Avignone E, Peyroutou R, Hirbec H, Audinat E, Rassendren F. Involvement of P2X4 receptors in hippocampal microglial activation after status epilepticus. Glia. 2013;61:1306–19.

    PubMed  Google Scholar 

  193. Vainchtein ID, Molofsky AV. Astrocytes and microglia: in sickness and in health. Trends Neurosci. 2020;43:1–11.

    Google Scholar 

  194. van der Hel WS, Notenboom RGE, Bos IWM, van Rijen PC, van Veelen CWM, de Graan PNE. Reduced glutamine synthetase in hippocampal areas with neuron loss in temporal lobe epilepsy. Neurology. 2005;64:326–33.

    PubMed  Google Scholar 

  195. van Scheppingen J, Mills JD, Zimmer TS, Broekaart DWM, Iori V, Bongaarts A, Anink JJ, Iyer AM, Korotkov A, Jansen FE, van Hecke W, Spliet WG, van Rijen PC, Baayen JC, Vezzani A, van Vliet EA, Aronica E. miR147b: a novel key regulator of interleukin 1 beta-mediated inflammation in human astrocytes. Glia. 2018;66:1082–97.

    PubMed  Google Scholar 

  196. van Vliet EA, Aronica E, Gorter JA. Blood–brain barrier dysfunction, seizures and epilepsy. Semin Cell Dev Biol. 2015;38:26–34.

    PubMed  Google Scholar 

  197. Varadkar S, Cross JH. Rasmussen syndrome and other inflammatory epilepsies. Semin Neurol. 2015;35:259–68.

    PubMed  Google Scholar 

  198. Verkhratsky A, Matteoli M, Parpura V, Mothet J-P, Zorec R. Astrocytes as secretory cells of the central nervous system: idiosyncrasies of vesicular secretion. EMBO J. 2016;35:239–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Verkhratsky A, Parpura V. Astrogliopathology in neurological, neurodevelopmental and psychiatric disorders. Neurobiol Dis. 2016;85:254–61.

    PubMed  Google Scholar 

  200. Vezzani A, Balosso S, Ravizza T. Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy. Nat Rev Neurol. 2019;15:459–72.

    CAS  PubMed  Google Scholar 

  201. Vezzani A, French J, Bartfai T, Baram TZ. The role of inflammation in epilepsy. Nat Rev Neurol. 2011;7:31–40.

    CAS  PubMed  Google Scholar 

  202. Volk DW. Role of microglia disturbances and immune-related marker abnormalities in cortical circuitry dysfunction in schizophrenia. Neurobiol Dis. 2017;99:58–65.

    CAS  PubMed  Google Scholar 

  203. Volterra A, Liaudet N, Savtchouk I. Astrocyte Ca2+ signalling: an unexpected complexity. Nat Rev Neurosci. 2014;15:327–35.

    CAS  PubMed  Google Scholar 

  204. Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci. 2009;29:3974–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Wallraff A, Kohling R, Heinemann U, Theis M, Willecke K, Steinhauser C. The impact of astrocytic gap junctional coupling on potassium buffering in the hippocampus. J Neurosci. 2006;26:5438–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Waltl I, Käufer C, Gerhauser I, Chhatbar C, Ghita L, Kalinke U, Löscher W. Microglia have a protective role in viral encephalitis-induced seizure development and hippocampal damage. Brain Behav Immun. 2018;74:186–204.

    PubMed  PubMed Central  Google Scholar 

  207. Walz W. Role of astrocytes in the clearance of excess extracellular potassium. Neurochem Int. 2000;36:291–300.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Wei Y-J, Guo W, Sun F-J, Fu W-L, Zheng D-H, Chen X, Li S, Zang Z-L, Zhang C-Q, Liu S-Y, Yang H. Increased expression and cellular localization of P2X7R in cortical lesions of patients with focal cortical dysplasia. J Neuropathol Exp Neurol. 2016;75:61–8.

    CAS  PubMed  Google Scholar 

  210. Weissberg I, Wood L, Kamintsky L, Vazquez O, Milikovsky DZ, Alexander A, Oppenheim H, Ardizzone C, Becker A, Frigerio F, Vezzani A, Buckwalter MS, Huguenard JR, Friedman A, Kaufer D. Albumin induces excitatory synaptogenesis through astrocytic TGF-β/ALK5 signaling in a model of acquired epilepsy following blood-brain barrier dysfunction. Neurobiol Dis. 2015;78:115–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Wolf SA, Boddeke HWGM, Kettenmann H. Microglia in physiology and disease. Annu Rev Physiol. 2017;79:619–43.

    CAS  PubMed  Google Scholar 

  212. Wu LJ, Stevens B, Duan S, MacVicar BA. Microglia in neuronal circuits. Neural Plast. 2013;2013:586426.

    PubMed  PubMed Central  Google Scholar 

  213. Wu W, Li Y, Wei Y, Bosco DB, Xie M, Zhao MG, Richardson JR, Wu LJ. Microglial depletion aggravates the severity of acute and chronic seizures in mice. Brain Behav Immun. 2020;89:245–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Xu Y, Zeng K, Han Y, Wang L, Chen D, Xi Z, Wang H, Wang X, Chen G. Altered expression of CX3CL1 in patients with epilepsy and in a rat model. Am J Pathol. 2012;180:1950–62.

    CAS  PubMed  Google Scholar 

  215. Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, Giffard RG, Barres BA. Genomic analysis of reactive astrogliosis. J Neurosci. 2012;32:6391–410.

    CAS  PubMed  PubMed Central  Google Scholar 

  216. Zhao X, Liao Y, Morgan S, Mathur R, Feustel P, Mazurkiewicz J, Qian J, Chang J, Mathern GW, Adamo MA, Ritaccio AL, Gruenthal M, Zhu X, Huang Y. Noninflammatory changes of microglia are sufficient to cause epilepsy. Cell Rep. 2018;22:2080–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Zhao Z, Nelson AR, Betsholtz C, Zlokovic BV. Establishment and dysfunction of the blood-brain barrier. Cell. 2015;163:1064–78.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. IGF, University of Montpellier, CNRS, INSERM, Montpellier, France

    Etienne Audinat & François Rassendren

Authors
  1. Etienne Audinat
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. François Rassendren
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Etienne Audinat .

Editor information

Editors and Affiliations

  1. Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, USA

    Damir Janigro

  2. INSERM, Strasbourg, France

    Astrid Nehlig

  3. Cerebrovascular and Glia Research, Department of Neuroscience, Institute of Functional Genomics (UMR 5203 CNRS – U 1191 INSERM, University of Montpellier), Montpellier, France

    Nicola Marchi

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Audinat, E., Rassendren, F. (2021). Glial Mechanisms of Inflammation During Seizures. In: Janigro, D., Nehlig, A., Marchi, N. (eds) Inflammation and Epilepsy: New Vistas. Progress in Inflammation Research, vol 88. Springer, Cham. https://doi.org/10.1007/978-3-030-67403-8_3

Download citation

Publish with us

Policies and ethics

Search

Navigation