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Glia in Epilepsy: An Overview

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The Biology of Glial Cells: Recent Advances

Abstract

Epilepsy is one of the most common neurological disorders affecting 1% of the world population and is characterized by recurrent, spontaneous seizures caused due to hyperexcitability and hypersynchrony of neurons. Nearly one-third of the patients having seizures are drug resistant that is they do not respond to antiepileptic drugs (AEDs); therefore, a deeper understanding of the underlying mechanisms is required to develop more effective therapies. Most of the AEDs target neuronal mechanisms, however, the glia outnumbers the neurons in the CNS and are involved in controlling diverse neuronal functions. The understanding of the role of glia in epilepsy is therefore pertinent for knowing the pathophysiology of epilepsy. Altered glial functions may promote epileptogenesis. Astrocyte and microglia activation, gliosis, and glial tumors are reported to be associated with the epilepsy. Astrocytes regulate water and K+ flow providing osmotic spatial buffering. The release of gliotransmitters like glutamate, adenosine, and ATP plays important roles in the pathophysiology. Astrocytes are intimately related to the blood vessels and regulate the blood-brain barrier functions by releasing chemical signals that maintain tight junction formation and their function. The brain microvasculature undergoes several alterations in epilepsy. Astrocytes are coupled with different cells via gap junctions (GJs) which provide cellular communication, regulate K+ and glutamate redistribution, and mediate synapse function and memory formation. Microglia, the innate immune cells of the CNS have crucial role in both physiological and pathological conditions. Glia-mediated inflammation has been known to promote epileptogenesis. The release of chemokines, pro-inflammatory cytokines like IL-β1, TNF-α, and many others, is reported to be associated with seizure frequency and disease duration in various epilepsy pathologies like mesial temporal sclerosis, focal cortical dysplasia, and Rasmussen’s encephalitis. Thus, the interplay between microglia and astrocytes is crucial in epileptogenesis. In this chapter, we aim to provide an overview of the current understanding of the role of astrocytes and microglia in the pathophysiology of epilepsy discussing their function in ion homeostasis, glutamate metabolism, gliotransmission, maintenance of the blood-brain barrier, and inflammation.

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References

  • Nagelhus EA, Mathiisen TM, Ottersen OP (2004) Aquaporin-4 in the central nervous system: cellular and subcellular distribution and coexpression with KIR4.1. Neuroscience 129:905–913

    Article  CAS  PubMed  Google Scholar 

  • Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FM (2007) Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci 10:1538–1543

    Article  CAS  PubMed  Google Scholar 

  • Ali I, Chugh D, Ekdahl CT (2015) Role of fractalkine-CX3CR1 pathway in seizure-induced microglial activation, neurodegeneration, and neuroblast production in the adult rat brain. Neurobiol Dis 74:194–203. https://doi.org/10.1016/j.nbd.2014.11.009. Epub 2014 Nov 21. PMID: 25461978

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Amiry-Moghaddam M, Williamson A, Palomba M, Eid T, de Lanerolle NC, Nagelhus EA, Adams ME, Froehner SC, Agre P, Ottersen OP (2003) Delayed K+ clearance associated with aquaporin-4 mislocalization: phenotypic defects in brains of alpha-syntrophin-null mice. Proc Natl Acad Sci U S A 100:13615–13620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Araque A, Carmignoto G, Haydon PG, Oliet SH, Robitaille R, Volterra A (2014) Gliotransmitters travel in time and space. Neuron 81:728–739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Araque A, Sanzgiri RP, Parpura V, Haydon PG (1998) Calcium elevation in astrocytes causes an NMDA receptor-dependent increase in the frequency of miniature synaptic currents in cultured hippocampal neurons. J Neurosci 18:6822–6829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aronica E, Gorter JA, Ijlst-Keizers H, Rozemuller AJ, Yankaya B, Leenstra S, Troost D (2003) Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins. Eur J Neurosci 17:2106–2118

    Article  PubMed  Google Scholar 

  • Aronica E, Ravizza T, Zurolo E, Vezzani A (2012) Astrocyte immune responses in epilepsy. Glia 60:1258–1268

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Aronica E, Yankaya B, Jansen GH, Leenstra S, van Veelen CW, Gorter JA, Troost D (2001) Ionotropic and metabotropic glutamate receptor protein expression in glioneuronal tumours from patients with intractable epilepsy. Neuropathol Appl Neurobiol 27:223–237

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arranz AM, Perkins KL, Irie F, Lewis DP, Hrabe J, Xiao F, Itano N, Kimata K, Hrabetova S, Yamaguchi Y (2014) Hyaluronan deficiency due to Has3 knock-out causes altered neuronal activity and seizures via reduction in brain extracellular space. J Neurosci 34:6164–6176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Balestrini S, Sisodiya SM (2018) Pharmacogenomics in epilepsy. Neurosci Lett 667:27–39

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Banerjee J, Chandra SP, Kurwale N, Tripathi M (2014) Epileptogenic networks and drug-resistant epilepsy: present and future perspectives of epilepsy research-utility for the epileptologist and the epilepsy surgeon. Ann Indian Acad Neurol 17:S134–S140

    Article  PubMed  PubMed Central  Google Scholar 

  • Banerjee J, Tripathi M, Sarat Chandra P (2013) Understanding complexities of synaptic transmission in medically intractable seizures: a paradigm of epilepsy research. Indian J Neurosurg 02:071–076

    Google Scholar 

  • Beach TG, Woodhurst WB, MacDonald DB, Jones MW (1995) Reactive microglia in hippocampal sclerosis associated with human temporal lobe epilepsy. Neurosci Lett 191:27–30

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  • Bezzi P, Domercq M, Brambilla L, Galli R, Schols D, De Clercq E, Vescovi A, Bagetta G, Kollias G, Meldolesi J, Volterra A (2001) CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity. Nat Neurosci 4:702–710

    Article  CAS  PubMed  Google Scholar 

  • Bianchi R, Wong RKS, Merlin LR (2012) Glutamate receptors in epilepsy: group I mGluR-mediated epileptogenesis. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV (eds) Jasper’s basic mechanisms of the epilepsies. National Center for Biotechnology Information (US), Bethesda, MD

    Google Scholar 

  • Binder DK, Nagelhus EA, Ottersen OP (2012) Aquaporin-4 and epilepsy. Glia 60:1203–1214

    Article  PubMed  Google Scholar 

  • Binder DK, Steinhäuser C (2006) Functional changes in astroglial cells in epilepsy. Glia 54:358–368

    Article  PubMed  Google Scholar 

  • Binder DK, Steinhäuser C (2017) Role of astrocyte dysfunction in epilepsy☆. In: Reference module in neuroscience and biobehavioral psychology. Elsevier, Amsterdam

    Google Scholar 

  • Binder DK, Yao X, Zador Z, Sick TJ, Verkman AS, Manley GT (2006) Increased seizure duration and slowed potassium kinetics in mice lacking aquaporin-4 water channels. Glia 53:631–636

    Article  PubMed  Google Scholar 

  • Boer K, Spliet WG, van Rijen PC, Redeker S, Troost D, Aronica E (2006) Evidence of activated microglia in focal cortical dysplasia. J Neuroimmunol 173:188–195

    Article  CAS  PubMed  Google Scholar 

  • Boison D (2016) Adenosinergic signaling in epilepsy. Neuropharmacology 104:131–139

    Article  CAS  PubMed  Google Scholar 

  • 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 (2018) RNAseq analysis of hippocampal microglia after kainic acid-induced seizures. Mol Brain 11:34

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bowser DN, Khakh BS (2004) ATP excites interneurons and astrocytes to increase synaptic inhibition in neuronal networks. J Neurosci 24:8606–8620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buckmaster PS, Abrams E, Wen X (2017) Seizure frequency correlates with loss of dentate gyrus GABAergic neurons in a mouse model of temporal lobe epilepsy. J Comp Neurol 525:2592–2610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buono RJ, Lohoff FW, Sander T, Sperling MR, O’Connor MJ, Dlugos DJ, Ryan SG, Golden GT, Zhao H, Scattergood TM, Berrettini WH, Ferraro TN (2004) Association between variation in the human KCNJ10 potassium ion channel gene and seizure susceptibility. Epilepsy Res 58:175–183

    Article  CAS  PubMed  Google Scholar 

  • Campbell SL, Hablitz JJ (2008) Decreased glutamate transport enhances excitability in a rat model of cortical dysplasia. Neurobiol Dis 32:254–261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Campbell SL, Hablitz JJ, Olsen ML (2014) Functional changes in glutamate transporters and astrocyte biophysical properties in a rodent model of focal cortical dysplasia. Front Cell Neurosci 8:425

    PubMed  PubMed Central  Google Scholar 

  • 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 (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9(7):917–924. https://doi.org/10.1038/nn1715. Epub 2006 Jun 18. PMID: 16732273

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  • Centeno M, Carmichael DW (2014) Network connectivity in epilepsy: resting state fMRI and EEG-fMRI contributions. Front Neurol 5:93

    Article  PubMed  PubMed Central  Google Scholar 

  • Chever O, Lee C-Y, Rouach N (2014) Astroglial connexin43 hemichannels tune basal excitatory synaptic transmission. J Neurosci 34:11228

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Choi J, Nordli DR Jr, Alden TD, DiPatri A Jr, Laux L, Kelley K, Rosenow J, Schuele SU, Rajaram V, Koh S (2009) Cellular injury and neuroinflammation in children with chronic intractable epilepsy. J Neuroinflammation 19(6):38. https://doi.org/10.1186/1742-2094-6-38. PMID: 20021679; PMCID: PMC2811703

    Article  CAS  Google Scholar 

  • Choi J, Min HJ, Shin JS (2011) Increased levels of HMGB1 and pro-inflammatory cytokines in children with febrile seizures. J Neuroinflammation 8:135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clarke LE, Barres BA (2013) Emerging roles of astrocytes in neural circuit development. Nat Rev Neurosci 14:311–321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clasadonte J, Haydon PG (2012) Astrocytes and epilepsy. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV (eds) Jasper’s basic mechanisms of the epilepsies. National Center for Biotechnology Information (US), Bethesda, MD

    Google Scholar 

  • Coulter DA, Steinhäuser C (2015) Role of astrocytes in epilepsy. Cold Spring Harb Perspect Med 5:a022434

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Crespel A, Coubes P, Rousset MC, Brana C, Rougier A, Rondouin G, Bockaert J, Baldy-Moulinier M, Lerner-Natoli M (2002) Inflammatory reactions in human medial temporal lobe epilepsy with hippocampal sclerosis. Brain Res 952:159–169

    Article  CAS  PubMed  Google Scholar 

  • De Bock M, Culot M, Wang N, Bol M, Decrock E, De Vuyst E, da Costa A, Dauwe I, Vinken M, Simon AM, Rogiers V, De Ley G, Evans WH, Bultynck G, Dupont G, Cecchelli R, Leybaert L (2011) Connexin channels provide a target to manipulate brain endothelial calcium dynamics and blood-brain barrier permeability. J Cereb Blood Flow Metab 31:1942–1957

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Deshpande T, Li T, Herde MK, Becker A, Vatter H, Schwarz MK, Henneberger C, Steinhäuser C, Bedner P (2017) Subcellular reorganization and altered phosphorylation of the astrocytic gap junction protein connexin43 in human and experimental temporal lobe epilepsy. Glia 65:1809–1820

    Article  PubMed  Google Scholar 

  • Devinsky O, Vezzani A, Najjar S, De Lanerolle NC, Rogawski MA (2013) Glia and epilepsy: excitability and inflammation. Trends Neurosci 36:174–184

    Article  CAS  PubMed  Google Scholar 

  • Dikow N, Maas B, Karch S, Granzow M, Janssen JW, Jauch A, Hinderhofer K, Sutter C, Schubert-Bast S, Anderlid BM, Dallapiccola B, Van der Aa N, Moog U (2014) 3p253 microdeletion of GABA transporters SLC6A1 and SLC6A11 results in intellectual disability, epilepsy and stereotypic behavior. Am J Med Genet A 164a:3061–3068

    Article  PubMed  CAS  Google Scholar 

  • Ding S, Fellin T, Zhu Y, Lee SY, Auberson YP, Meaney DF, Coulter DA, Carmignoto G, Haydon PG (2007) Enhanced astrocytic Ca2+ signals contribute to neuronal excitotoxicity after status epilepticus. J Neurosci 27:10674–10684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ding Z, Mathur V, Ho PP, James ML, Lucin KM, Hoehne A, Alabsi H, Gambhir SS, Steinman L, Luo J, Wyss-Coray T (2014) Antiviral drug ganciclovir is a potent inhibitor of microglial proliferation and neuroinflammation. J Exp Med 211(2):189–198. https://doi.org/10.1084/jem.20120696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dityatev A (2010) Remodeling of extracellular matrix and epileptogenesis. Epilepsia 51(Suppl 3):61–65

    Article  CAS  PubMed  Google Scholar 

  • Dixit AB, Banerjee J, Tripathi M, Chandra PS (2015) Presurgical epileptogenic network analysis: a way to enhance epilepsy surgery outcome. Neurol India 63:743–750

    Article  PubMed  Google Scholar 

  • Dixit AB, Tripathi M, Chandra PS, Banerjee J (2016) Molecular biomarkers in drug-resistant epilepsy: facts & possibilities. Int J Surg (London, England) 36:483–491

    Article  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Djukic M, Mildner A, Schmidt H, Czesnik D, Brück W, Priller J, Nau R, Prinz M (2006) Circulating monocytes engraft in the brain, differentiate into microglia and contribute to the pathology following meningitis in mice. Brain 129:2394–2403

    Article  PubMed  Google Scholar 

  • Dubey D, McRae PA, Rankin-Gee EK, Baranov E, Wandrey L, Rogers S, Porter BE (2017) Increased metalloproteinase activity in the hippocampus following status epilepticus. Epilepsy Res 132:50–58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • During MJ, Spencer DD (1992) Adenosine: a potential mediator of seizure arrest and postictal refractoriness. Ann Neurol 32:618–624

    Article  CAS  PubMed  Google Scholar 

  • During MJ, Spencer DD (1993) Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet (London, England) 341:1607–1610

    Article  CAS  Google Scholar 

  • Eid T, Ghosh A, Wang Y, Beckström H, Zaveri HP, Lee TS, Lai JC, Malthankar-Phatak GH, de Lanerolle NC (2008a) Recurrent seizures and brain pathology after inhibition of glutamine synthetase in the hippocampus in rats. Brain 131:2061–2070

    Article  PubMed  PubMed Central  Google Scholar 

  • Eid T, Gruenbaum SE, Dhaher R, Lee TW, Zhou Y, Danbolt NC (2016) The glutamate-glutamine cycle in epilepsy. Adv Neurobiol 13:351–400

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Eid T, Williamson A, Lee TS, Petroff OA, de Lanerolle NC (2008b) Glutamate and astrocytes—key players in human mesial temporal lobe epilepsy? Epilepsia 49(Suppl 2):42–52

    Article  CAS  PubMed  Google Scholar 

  • Fabene PF, Bramanti P, Constantin G (2010) The emerging role for chemokines in epilepsy. J Neuroimmunol 224:22–27

    Article  CAS  PubMed  Google Scholar 

  • Fang J, Han D, Hong J, Tan Q, Tian Y (2012) The chemokine, macrophage inflammatory protein-2γ, reduces the expression of glutamate transporter-1 on astrocytes and increases neuronal sensitivity to glutamate excitotoxicity. J Neuroinflammation 9:267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fang M, Xi ZQ, Wu Y, Wang XF (2011) A new hypothesis of drug refractory epilepsy: neural network hypothesis. Med Hypotheses 76:871–876

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Feng L, Murugan M, Bosco DB, Liu Y, Peng J, Worrell GA, Wang HL, Ta LE, Richardson JR, Shen Y, Wu LJ (2019) Microglial proliferation and monocyte infiltration contribute to microgliosis following status epilepticus. Glia 67:1434–1448

    PubMed  PubMed Central  Google Scholar 

  • Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, Engel J Jr, Forsgren L, French JA, Glynn M, Hesdorffer DC, Lee BI, Mathern GW, Moshe SL, Perucca E, Scheffer IE, Tomson T, Watanabe M, Wiebe S (2014) ILAE official report: a practical clinical definition of epilepsy. Epilepsia 55:475–482

    Article  PubMed  Google Scholar 

  • Fisher RS, Cross JH, French JA, Higurashi N, Hirsch E, Jansen FE, Lagae L, Moshé SL, Peltola J, Roulet Perez E, Scheffer IE, Zuberi SM (2017) Operational classification of seizure types by the International League Against Epilepsy: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 58:522–530

    Article  PubMed  Google Scholar 

  • Flügel A, Bradl M, Kreutzberg GW, Graeber MB (2001) Transformation of donor-derived bone marrow precursors into host microglia during autoimmune CNS inflammation and during the retrograde response to axotomy. J Neurosci Res 66:74–82

    Article  PubMed  Google Scholar 

  • Gabriel S, Njunting M, Pomper JK, Merschhemke M, Sanabria ER, Eilers A, Kivi A, Zeller M, Meencke HJ, Cavalheiro EA, Heinemann U, Lehmann TN (2004) Stimulus and potassium-induced epileptiform activity in the human dentate gyrus from patients with and without hippocampal sclerosis. J Neurosci 24:10416–10430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gharaylou Z, Tafakhori A, Agah E, Aghamollaii V, Kebriaeezadeh A, Hadjighassem M (2019) A preliminary study evaluating the safety and efficacy of bumetanide, an NKCC1 inhibitor, in patients with drug-resistant epilepsy. CNS Drugs 33:283–291

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Goldberg EM, Coulter DA (2013) Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction. Nat Rev Neurosci 14:337–349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gomes CV, Kaster MP, Tomé AR, Agostinho PM, Cunha RA (2011) Adenosine receptors and brain diseases: neuroprotection and neurodegeneration. Biochim Biophys Acta 1808:1380–1399

    Article  CAS  PubMed  Google Scholar 

  • Griffiths MR, Gasque P, Neal JW (2009) The multiple roles of the innate immune system in the regulation of apoptosis and inflammation in the brain. J Neuropathol Exp Neurol 68:217–226

    Article  CAS  PubMed  Google Scholar 

  • Hanak TJ, Libbey JE, Doty DJ, Sim JT, DePaula-Silva AB, Fujinami RS (2019) Positive modulation of mGluR5 attenuates seizures and reduces TNF-α(+) macrophages and microglia in the brain in a murine model of virus-induced temporal lobe epilepsy. Exp Neurol 311:194–204

    Article  CAS  PubMed  Google Scholar 

  • Heinemann U, Lux HD (1977) Ceiling of stimulus induced rises in extracellular potassium concentration in the cerebral cortex of cat. Brain Res 120:231–249

    Article  CAS  PubMed  Google Scholar 

  • Henneberger C, Steinhäuser C (2016) Astrocytic TLR4 at the crossroads of inflammation and seizure susceptibility. J Cell Biol 215:607–609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heuser K, Eid T, Lauritzen F, Thoren AE, Vindedal GF, Taubøll E, Gjerstad L, Spencer DD, Ottersen OP, Nagelhus EA, de Lanerolle NC (2012) Loss of perivascular Kir4.1 potassium channels in the sclerotic hippocampus of patients with mesial temporal lobe epilepsy. J Neuropathol Exp Neurol 71:814–825

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Hu C, Tao L, Cao X, Chen L (2020) The solute carrier transporters and the brain: physiological and pharmacological implications. Asian J Pharm Sci 15:131–144

    Article  PubMed  Google Scholar 

  • Hubbard JA, Binder DK (2016a) Chapter 2—Astrocytes in the mammalian brain. In: Hubbard JA, Binder DK (eds) Astrocytes and epilepsy. Academic, San Diego, pp 39–51

    Chapter  Google Scholar 

  • Hubbard JA, Binder DK (2016b) Chapter 3—Gliotransmitters. In: Hubbard JA, Binder DK (eds) Astrocytes and epilepsy. Academic, San Diego, pp 53–73

    Chapter  Google Scholar 

  • Hubbard JA, Binder DK (2016c) Chapter 6—Astrocyte calcium signaling. In: Hubbard JA, Binder DK (eds) Astrocytes and epilepsy. Academic, San Diego, pp 125–145

    Chapter  Google Scholar 

  • Hubbard JA, Binder DK (2016d) Chapter 8—Water channels. In: Hubbard JA, Binder DK (eds) Astrocytes and epilepsy. Academic, San Diego, pp 171–195

    Chapter  Google Scholar 

  • Hubbard JA, Binder DK (2016e) Chapter 9—Glutamate metabolism. In: Hubbard JA, Binder DK (eds) Astrocytes and epilepsy. Academic, San Diego, pp 197–224

    Chapter  Google Scholar 

  • Hubbard JA, Binder DK (2016f) Chapter 11—Gap junctions. In: Hubbard JA, Binder DK (eds) Astrocytes and epilepsy. Academic, San Diego, pp 265–289

    Chapter  Google Scholar 

  • Hubbard JA, Binder DK (2016g) Chapter 12—Blood–brain barrier disruption. In: Hubbard JA, Binder DK (eds) Astrocytes and epilepsy. Academic, San Diego, pp 291–311

    Chapter  Google Scholar 

  • Ivens S, Kaufer D, Flores LP, Bechmann I, Zumsteg D, Tomkins O, Seiffert E, Heinemann U, Friedman A (2007) TGF-beta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. Brain 130:535–547

    Article  PubMed  Google Scholar 

  • Jiang E, Yan X, Weng HR (2012) Glial glutamate transporter and glutamine synthetase regulate GABAergic synaptic strength in the spinal dorsal horn. J Neurochem 121:526–536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaczor P, Rakus D, Mozrzymas JW (2015) Neuron-astrocyte interaction enhance GABAergic synaptic transmission in a manner dependent on key metabolic enzymes. Front Cell Neurosci 9:120

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kambli L, Bhatt LK, Oza M, Prabhavalkar K (2017) Novel therapeutic targets for epilepsy intervention. Seizure 51:27–34

    Article  PubMed  Google Scholar 

  • Kan AA, van der Hel WS, Kolk SM, Bos IW, Verlinde SA, van Nieuwenhuizen O, de Graan PN (2012) Prolonged increase in rat hippocampal chemokine signalling after status epilepticus. J Neuroimmunol 245:15–22

    Article  CAS  PubMed  Google Scholar 

  • Kandratavicius L, Rosa-Neto P, Monteiro MR, Guiot MC, Assirati JA Jr, Carlotti CG Jr, Kobayashi E, Leite JP (2013) Distinct increased metabotropic glutamate receptor type 5 (mGluR5) in temporal lobe epilepsy with and without hippocampal sclerosis. Hippocampus 23:1212–1230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I (2017) A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169:1276–1290.e17

    Article  CAS  PubMed  Google Scholar 

  • Kim JH, Je S, Petroff OA, Spencer SS, Hwang JY, Spencer DDJE (2004) Hippocampal glial density in temporal lobe epilepsy. Epilepsia 45:S33–S34

    Article  Google Scholar 

  • Kim SY, Buckwalter M, Soreq H, Vezzani A, Kaufer D (2012) Blood-brain barrier dysfunction-induced inflammatory signaling in brain pathology and epileptogenesis. Epilepsia 53(Suppl 6):37–44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim SY, Porter BE, Friedman A, Kaufer D (2016) A potential role for glia-derived extracellular matrix remodeling in postinjury epilepsy. J Neurosci Res 94:794–803

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kofuji P, Newman EA (2004) Potassium buffering in the central nervous system. Neuroscience 129:1045–1056

    Article  CAS  PubMed  Google Scholar 

  • Koubeissi M (2013) Neuropathology of the blood-brain barrier in epilepsy: support to the transport hypothesis of pharmacoresistance. Epilepsy Curr 13:169–171

    Article  PubMed  PubMed Central  Google Scholar 

  • Kucheryavykh YV, Kucheryavykh LY, Nichols CG, Maldonado HM, Baksi K, Reichenbach A, Skatchkov SN, Eaton MJ (2007) Downregulation of Kir4.1 inward rectifying potassium channel subunits by RNAi impairs potassium transfer and glutamate uptake by cultured cortical astrocytes. Glia 55:274–281

    Article  CAS  PubMed  Google Scholar 

  • Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, Moshé SL, Perucca E, Wiebe S, French J (2010) Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 51:1069–1077

    Article  CAS  PubMed  Google Scholar 

  • Lau LW, Cua R, Keough MB, Haylock-Jacobs S, Yong VW (2013) Pathophysiology of the brain extracellular matrix: a new target for remyelination. Nat Rev Neurosci 14:722–729

    Article  CAS  PubMed  Google Scholar 

  • Lee DJ, Hsu MS, Seldin MM, Arellano JL, Binder DK (2012) Decreased expression of the glial water channel aquaporin-4 in the intrahippocampal kainic acid model of epileptogenesis. Exp Neurol 235:246–255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee SG, Su ZZ, Emdad L, Gupta P, Sarkar D, Borjabad A, Volsky DJ, Fisher PB (2008) Mechanism of ceftriaxone induction of excitatory amino acid transporter-2 expression and glutamate uptake in primary human astrocytes. J Biol Chem 283:13116–13123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Löscher W, Friedman A (2020) Structural, molecular, and functional alterations of the blood-brain barrier during epileptogenesis and epilepsy: a cause, consequence, or both? Int J Mol Sci 21(2):591

    Article  PubMed Central  CAS  Google Scholar 

  • Löscher W, Luna-Tortós C, Römermann K, Fedrowitz M (2011) Do ATP-binding cassette transporters cause pharmacoresistance in epilepsy? Problems and approaches in determining which antiepileptic drugs are affected. Curr Pharm Des 17:2808–2828

    Article  PubMed  Google Scholar 

  • Löscher W, Potschka H (2005) Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci 6:591–602

    Article  PubMed  CAS  Google Scholar 

  • Löscher W, Puskarjov M, Kaila K (2013) Cation-chloride cotransporters NKCC1 and KCC2 as potential targets for novel antiepileptic and antiepileptogenic treatments. Neuropharmacology 69:62–74

    Article  PubMed  CAS  Google Scholar 

  • Lykke K, Töllner K, Feit PW, Erker T, MacAulay N, Löscher W (2016) The search for NKCC1-selective drugs for the treatment of epilepsy: structure-function relationship of bumetanide and various bumetanide derivatives in inhibiting the human cation-chloride cotransporter NKCC1A. Epilepsy Behav 59:42–49

    Article  PubMed  Google Scholar 

  • Magistretti PJ, Allaman I (2015) A cellular perspective on brain energy metabolism and functional imaging. Neuron 86:883–901

    Article  CAS  PubMed  Google Scholar 

  • Margineanu DG, Klitgaard H (2009) Mechanisms of drug resistance in epilepsy: relevance for antiepileptic drug discovery. Expert Opin Drug Discov 4:23–32

    Article  CAS  PubMed  Google Scholar 

  • Matsuda T, Murao N, Katano Y, Juliandi B, Kohyama J, Akira S, Kawai T, Nakashima K (2015) TLR9 signalling in microglia attenuates seizure-induced aberrant neurogenesis in the adult hippocampus. Nat Commun 6:6514–6514

    Article  CAS  PubMed  Google Scholar 

  • Mattison KA, Butler KM, Inglis GAS, Dayan O, Boussidan H, Bhambhani V, Philbrook B, da Silva C, Alexander JJ, Kanner BI, Escayg A (2018) SLC6A1 variants identified in epilepsy patients reduce γ-aminobutyric acid transport. Epilepsia 59:e135–e141

    Article  CAS  PubMed  Google Scholar 

  • Medici V, Frassoni C, Tassi L, Spreafico R, Garbelli R (2011) Aquaporin 4 expression in control and epileptic human cerebral cortex. Brain Res 1367:330–339

    Article  CAS  PubMed  Google Scholar 

  • Merlini M, Rafalski VA, Ma K, Kim K-Y, Bushong EA, Rios Coronado PE, Yan Z, Mendiola AS, Sozmen EG, Ryu JK, Haberl MG, Madany M, Sampson DN, Petersen MA, Bardehle S, Tognatta R, Dean T, Acevedo RM, Cabriga B, Thomas R et al (2021) Microglial Gi-dependent dynamics regulate brain network hyperexcitability. Nat Neurosci 24:19–23

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miskin C, Hasbani DM, Epilepticus S (2014) Immunologic and inflammatory mechanisms. Semin Pediatr Neurol 21(3):221–225. ISSN 1071-9091. https://doi.org/10.1016/j.spen.2014.09.001

    Article  PubMed  Google Scholar 

  • Moinfar Z, Dambach H, Faustmann PM (2014) Influence of drugs on gap junctions in glioma cell lines and primary astrocytes in vitro. Front Physiol 5:186

    Article  PubMed  PubMed Central  Google Scholar 

  • Møller RS, Schneider LM, Hansen CP, Bugge M, Ullmann R, Tommerup N, Tümer Z (2008) Balanced translocation in a patient with severe myoclonic epilepsy of infancy disrupts the sodium channel gene SCN1A. Epilepsia 49:1091–1094

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Moore YE, Kelley MR, Brandon NJ, Deeb TZ, Moss SJ (2017) Seizing control of KCC2: a new therapeutic target for epilepsy. Trends Neurosci 40:555–571

    Article  CAS  PubMed  Google Scholar 

  • Mylvaganam S, Ramani M, Krawczyk M, Carlen PL (2014) Roles of gap junctions, connexins, and pannexins in epilepsy. Front Physiol 5:172

    Article  PubMed  PubMed Central  Google Scholar 

  • Navarrete M, Perea G, Maglio L, Pastor J, García de Sola R, Araque A (2013) Astrocyte calcium signal and gliotransmission in human brain tissue. Cereb Cortex (New York, NY: 1991) 23:1240–1246

    Google Scholar 

  • Nicholson C, Syková E (1998) Extracellular space structure revealed by diffusion analysis. Trends Neurosci 21:207–215

    Article  CAS  PubMed  Google Scholar 

  • Notenboom RG, Hampson DR, Jansen GH, van Rijen PC, van Veelen CW, van Nieuwenhuizen O, de Graan PN (2006) Up-regulation of hippocampal metabotropic glutamate receptor 5 in temporal lobe epilepsy patients. Brain 129:96–107

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Onodera M, Meyer J, Furukawa K, Hiraoka Y, Aida T, Tanaka K, Tanaka KF, Rose CR, Matsui K (2021) Exacerbation of epilepsy by astrocyte alkalization and gap junction uncoupling. J Neurosci 41:2106–2118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Orellana JA, Retamal MA, Moraga-Amaro R, Stehberg J (2016) Role of astroglial hemichannels and pannexons in memory and neurodegenerative diseases. Front Integr Neurosci 10:26

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Orellana JA, Stehberg J (2014) Hemichannels: new roles in astroglial function. Front Physiol 5:193

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pack AM (2019) Epilepsy overview and revised classification of seizures and epilepsies. Continuum (Minneapolis, Minn) 25:306–321

    Google Scholar 

  • Papadopoulos MC, Verkman AS (2013) Aquaporin water channels in the nervous system. Nat Rev Neurosci 14:265–277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parpura V, Basarsky TA, Liu F, Jeftinija K, Jeftinija S, Haydon PG (1994) Glutamate-mediated astrocyte-neuron signalling. Nature 369:744–747

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patching SG (2017) Glucose transporters at the blood-brain barrier: function, regulation and gateways for drug delivery. Mol Neurobiol 54:1046–1077

    Article  CAS  PubMed  Google Scholar 

  • Patel DC, Tewari BP, Chaunsali L, Sontheimer H (2019) Neuron-glia interactions in the pathophysiology of epilepsy. Nat Rev Neurosci 20:282–297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pernhorst K, Herms S, Hoffmann P, Cichon S, Schulz H, Sander T, Schoch S, Becker AJ, Grote A (2013) TLR4, ATF-3 and IL8 inflammation mediator expression correlates with seizure frequency in human epileptic brain tissue. Seizure 22:675–678

    Article  PubMed  Google Scholar 

  • Peterson AR, Binder DK (2020) Astrocyte glutamate uptake and signaling as novel targets for antiepileptogenic therapy. Front Neurol 11:1006

    Article  PubMed  PubMed Central  Google Scholar 

  • Petroff OA, Errante LD, Rothman DL, Kim JH, Spencer DD (2002) Glutamate-glutamine cycling in the epileptic human hippocampus. Epilepsia 43:703–710

    Article  CAS  PubMed  Google Scholar 

  • Pollock E, Everest M, Brown A, Poulter MO (2014) Metalloproteinase inhibition prevents inhibitory synapse reorganization and seizure genesis. Neurobiol Dis 70:21–31

    Article  CAS  PubMed  Google Scholar 

  • Ramos-Lizana J, Aguilera-López P, Aguirre-Rodríguez J, Cassinello-García E (2009) Response to sequential treatment schedules in childhood epilepsy: risk for development of refractory epilepsy. Seizure 18:620–624

    Article  CAS  PubMed  Google Scholar 

  • Rankin-Gee EK, McRae PA, Baranov E, Rogers S, Wandrey L, Porter BE (2015) Perineuronal net degradation in epilepsy. Epilepsia 56:1124–1133

    Article  CAS  PubMed  Google Scholar 

  • Ravizza T, Gagliardi B, Noé F, Boer K, Aronica E, Vezzani A (2008) Innate and adaptive immunity during epileptogenesis and spontaneous seizures: evidence from experimental models and human temporal lobe epilepsy. Neurobiol Dis 29:142–160

    Article  CAS  PubMed  Google Scholar 

  • Ravizza T, Rizzi M, Perego C, Richichi C, Velísková J, Moshé SL, De Simoni MG, Vezzani A (2005) Inflammatory response and glia activation in developing rat hippocampus after status epilepticus. Epilepsia 46(Suppl 5):113–117

    Article  CAS  PubMed  Google Scholar 

  • Rempe RG, Hartz AMS, Soldner ELB, Sokola BS, Alluri SR, Abner EL, Kryscio RJ, Pekcec A, Schlichtiger J, Bauer B (2018) Matrix metalloproteinase-mediated blood-brain barrier dysfunction in epilepsy. J Neurosci 38:4301–4315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rizzi M, Perego C, Aliprandi M, Richichi C, Ravizza T, Colella D, Velískŏvá J, Moshé SL, De Simoni MG, Vezzani A (2003) Glia activation and cytokine increase in rat hippocampus by kainic acid-induced status epilepticus during postnatal development. Neurobiol Dis 14:494–503

    Article  CAS  PubMed  Google Scholar 

  • Robel S, Buckingham SC, Boni JL, Campbell SL, Danbolt NC, Riedemann T, Sutor B, Sontheimer H (2015) Reactive astrogliosis causes the development of spontaneous seizures. J Neurosci 35:3330–3345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rogawski MA, Löscher W (2004) The neurobiology of antiepileptic drugs. Nat Rev Neurosci 5:553–564

    Article  CAS  PubMed  Google Scholar 

  • Rogove AD, Tsirka SE. Neurotoxic responses by microglia elicited by excitotoxic injury in the mouse hippocampus. Curr Biol. 1998 Jan 1;8(1):19-25. doi: 10.1016/s0960-9822(98)70016-8. PMID: 9427623.

    Google Scholar 

  • Roseti C, Fucile S, Lauro C, Martinello K, Bertollini C, Esposito V, Mascia A, Catalano M, Aronica E, Limatola C, Palma E (2013) Fractalkine/CX3CL1 modulates GABAA currents in human temporal lobe epilepsy. Epilepsia 54:1834–1844

    Article  CAS  PubMed  Google Scholar 

  • 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 (2017) Seizure activity per se does not induce tissue damage markers in human neocortical focal epilepsy. Ann Neurol 82:331–341

    Article  CAS  PubMed  Google Scholar 

  • Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, Jin L, Dykes Hoberg M, Vidensky S, Chung DS, Toan SV, Bruijn LI, Su ZZ, Gupta P, Fisher PB (2005) Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433:73–77

    Article  CAS  PubMed  Google Scholar 

  • Sada N, Lee S, Katsu T, Otsuki T, Inoue T (2015) Epilepsy treatment. Targeting LDH enzymes with a stiripentol analog to treat epilepsy. Science 347:1362–1367

    Article  CAS  PubMed  Google Scholar 

  • Salar S, Maslarova A, Lippmann K, Nichtweiss J, Weissberg I, Sheintuch L, Kunz WS, Shorer Z, Friedman A, Heinemann U (2014) Blood-brain barrier dysfunction can contribute to pharmacoresistance of seizures. Epilepsia 55:1255–1263

    Article  CAS  PubMed  Google Scholar 

  • Sarac S, Afzal S, Broholm H, Madsen FF, Ploug T, Laursen H (2009) Excitatory amino acid transporters EAAT-1 and EAAT-2 in temporal lobe and hippocampus in intractable temporal lobe epilepsy. APMIS 117:291–301

    Article  CAS  PubMed  Google Scholar 

  • Sarmast ST, Abdullahi AM, Jahan N (2020) Current classification of seizures and epilepsies: scope, limitations and recommendations for future action. Cureus 12:e10549

    PubMed  PubMed Central  Google Scholar 

  • Schousboe A, Scafidi S, Bak LK, Waagepetersen HS, McKenna MC (2014) Glutamate metabolism in the brain focusing on astrocytes. Adv Neurobiol 11:13–30

    Article  PubMed  PubMed Central  Google Scholar 

  • Seifert G, Carmignoto G, Steinhäuser C (2010) Astrocyte dysfunction in epilepsy. Brain Res Rev 63:212–221

    Article  CAS  PubMed  Google Scholar 

  • Seiffert E, Dreier JP, Ivens S, Bechmann I, Tomkins O, Heinemann U, Friedman A (2004) Lasting blood-brain barrier disruption induces epileptic focus in the rat somatosensory cortex. J Neurosci 24:7829–7836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sheng J, Liu S, Qin H, Li B, Zhang X (2018) Drug-resistant epilepsy and surgery. Curr Neuropharmacol 16:17–28

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shorvon SD, Goodridge DM (2013) Longitudinal cohort studies of the prognosis of epilepsy: contribution of the National General Practice Study of Epilepsy and other studies. Brain 136:3497–3510

    Article  PubMed  Google Scholar 

  • Simard AR, Rivest S (2004) Bone marrow stem cells have the ability to populate the entire central nervous system into fully differentiated parenchymal microglia. FASEB J 18:998–1000

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Sontheimer H (2015) Chapter 3—Seizure disorders and epilepsy. In: Sontheimer H (ed) Diseases of the nervous system. Academic, San Diego, pp 61–95

    Chapter  Google Scholar 

  • Sosunov AA, Guilfoyle E, Wu X, McKhann GM II, Goldman JE (2013) Phenotypic conversions of “protoplasmic” to “reactive” astrocytes in Alexander disease. J Neurosci 33:7439–7450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spiciarich MC, von Gaudecker JR, Jurasek L, Clarke DF, Burneo J, Vidaurre J (2019) Global health and epilepsy: update and future directions. Curr Neurol Neurosci Rep 19:30

    Article  PubMed  Google Scholar 

  • Stafstrom CE, Carmant L (2015) Seizures and epilepsy: an overview for neuroscientists. Cold Spring Harbor Perspect Med 5(6):a022426

    Article  CAS  Google Scholar 

  • Steinhäuser C, Seifert G, Bedner P (2012) Astrocyte dysfunction in temporal lobe epilepsy: K+ channels and gap junction coupling. Glia 60:1192–1202

    Article  PubMed  Google Scholar 

  • Stergachis AB, Pujol-Giménez J, Gyimesi G, Fuster D, Albano G, Troxler M, Picker J, Rosenberg PA, Bergin A, Peters J, El Achkar CM, Harini C, Manzi S, Rotenberg A, Hediger MA, Rodan LH (2019) Recurrent SLC1A2 variants cause epilepsy via a dominant negative mechanism. Ann Neurol 85:921–926

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Streit WJ, Mrak RE, Griffin WS (2004) Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation 1:14

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sun DA, Sombati S, Blair RE, DeLorenzo RJ (2002) Calcium-dependent epileptogenesis in an in vitro model of stroke-induced “epilepsy”. Epilepsia 43:1296–1305

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Thakran S, Guin D, Singh P, Singh P, Kukal S, Rawat C, Yadav S, Kushwaha SS, Srivastava AK, Hasija Y, Saso L, Ramachandran S, Kukreti R (2020) Genetic landscape of common epilepsies: advancing towards precision in treatment. Int J Mol Sci 21:7784

    Article  CAS  PubMed Central  Google Scholar 

  • Tian D-S, Peng J, Murugan M, Feng L-J, Liu J-L, Eyo UB, Zhou L-J, Mogilevsky R, Wang W, Wu L-J (2017) Chemokine CCL2-CCR2 signaling induces neuronal cell death via STAT3 activation and IL-1β production after status epilepticus. J Neurosci 37:7878–7892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tian GF, Azmi H, Takano T, Xu Q, Peng W, Lin J, Oberheim N, Lou N, Wang X, Zielke HR, Kang J, Nedergaard M (2005) An astrocytic basis of epilepsy. Nat Med 11:973–981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Uhlmann EJ, Wong M, Baldwin RL, Bajenaru ML, Onda H, Kwiatkowski DJ, Yamada K, Gutmann DH (2002) Astrocyte-specific TSC1 conditional knockout mice exhibit abnormal neuronal organization and seizures. Ann Neurol 52:285–296

    Article  CAS  PubMed  Google Scholar 

  • Ulu MO, Tanriverdi T, Oz B, Biceroglu H, Isler C, Eraslan BS, Ozkara C, Ozyurt E, Uzan M (2010) The expression of astroglial glutamate transporters in patients with focal cortical dysplasia: an immunohistochemical study. Acta Neurochir 152:845–853

    Article  PubMed  Google Scholar 

  • Umpierre AD, West PJ, White JA, Wilcox KS (2019) Conditional knock-out of mGluR5 from astrocytes during epilepsy development impairs high-frequency glutamate uptake. J Neurosci 39:727–742

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vajda Z, Pedersen M, Füchtbauer EM, Wertz K, Stødkilde-Jørgensen H, Sulyok E, Dóczi T, Neely JD, Agre P, Frøkiaer J, Nielsen S (2002) Delayed onset of brain edema and mislocalization of aquaporin-4 in dystrophin-null transgenic mice. Proc Natl Acad Sci U S A 99:13131–13136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van der Hel WS, Notenboom RG, Bos IW, van Rijen PC, van Veelen CW, de Graan PN (2005) Reduced glutamine synthetase in hippocampal areas with neuron loss in temporal lobe epilepsy. Neurology 64:326–333

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • van Vliet EA, da Costa Araújo S, Redeker S, van Schaik R, Aronica E, Gorter JA (2007) Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy. Brain 130:521–534

    Article  PubMed  Google Scholar 

  • Vandenberg RJ, Ryan RM (2013) Mechanisms of glutamate transport. Physiol Rev 93:1621–1657

    Article  CAS  PubMed  Google Scholar 

  • Vargas-Sánchez K, Mogilevskaya M, Rodríguez-Pérez J, Rubiano MG, Javela JJ, González-Reyes RE (2018) Astroglial role in the pathophysiology of status epilepticus: an overview. Oncotarget 9:26954–26976

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Verkhratsky A, Parpura V, Pekna M, Pekny M, Sofroniew M (2014) Glia in the pathogenesis of neurodegenerative diseases. Biochem Soc Trans 42:1291–1301

    Article  CAS  PubMed  Google Scholar 

  • Vezzani A, Aronica E, Mazarati A, Pittman QJ (2013a) Epilepsy and brain inflammation. Exp Neurol 244:11–21

    Article  CAS  PubMed  Google Scholar 

  • Vezzani A, Bartfai T, Bianchi M, Rossetti C, French J (2011a) Therapeutic potential of new antiinflammatory drugs. Epilepsia 52(Suppl 8):67–69

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Vezzani A, Friedman A (2011) Brain inflammation as a biomarker in epilepsy. Biomark Med 5:607–614

    Article  CAS  PubMed  Google Scholar 

  • Vezzani A, Friedman A, Dingledine RJ (2013b) The role of inflammation in epileptogenesis. Neuropharmacology 69:16–24

    Article  CAS  PubMed  Google Scholar 

  • Vezzani A, Maroso M, Balosso S, Sanchez MA, Bartfai T (2011c) IL-1 receptor/Toll-like receptor signaling in infection, inflammation, stress and neurodegeneration couples hyperexcitability and seizures. Brain Behav Immun 25:1281–1289

    Article  CAS  PubMed  Google Scholar 

  • Vezzani A, Moneta D, Conti M, Richichi C, Ravizza T, De Luigi A, De Simoni MG, Sperk G, Andell-Jonsson S, Lundkvist J, Iverfeldt K, Bartfai T (2000) Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice. Proc Natl Acad Sci U S A 97:11534–11539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vezzani A, Viviani B (2015) Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability. Neuropharmacology 96:70–82

    Article  CAS  PubMed  Google Scholar 

  • Volterra A, Meldolesi J (2005) Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci 6:626–640

    Article  CAS  PubMed  Google Scholar 

  • Voss LJ, Jacobson G, Sleigh JW, Steyn-Ross A, Steyn-Ross M (2009) Excitatory effects of gap junction blockers on cerebral cortex seizure-like activity in rats and mice. Epilepsia 50:1971–1978

    Article  CAS  PubMed  Google Scholar 

  • Walker L, Sills GJ (2012) Inflammation and epilepsy: the foundations for a new therapeutic approach in epilepsy? Epilepsy Curr 12:8–12

    Article  PubMed  PubMed Central  Google Scholar 

  • Wallraff A, Köhling R, Heinemann U, Theis M, Willecke K, Steinhäuser C (2006) The impact of astrocytic gap junctional coupling on potassium buffering in the hippocampus. J Neurosci 26:5438–5447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang DD et al (2012) Minocycline- and tetracycline-class antibiotics are protective against partial seizures in vivo. Epilepsy Behav 24(3):314–318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 (2015) Albumin induces excitatory synaptogenesis through astrocytic TGF-β/ALK5 signaling in a model of acquired epilepsy following blood-brain barrier dysfunction. Neurobiol Dis 78:115–125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woodcock T, Morganti-Kossmann MC (2013) The role of markers of inflammation in traumatic brain injury. Front Neurol 4:18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu Y, Wang X, Mo X, Xi Z, Xiao F, Li J, Zhu X, Luan G, Wang Y, Li Y, Zhang J (2008) Expression of monocyte chemoattractant protein-1 in brain tissue of patients with intractable epilepsy. Clin Neuropathol 27(2):55–63. https://doi.org/10.5414/npp27055. PMID: 18402383

    Article  CAS  PubMed  Google Scholar 

  • Wu XL, Tang YC, Lu QY, Xiao XL, Song TB, Tang FR (2015) Astrocytic Cx 43 and Cx 40 in the mouse hippocampus during and after pilocarpine-induced status epilepticus. Exp Brain Res 233:1529–1539

    Article  CAS  PubMed  Google Scholar 

  • Xu Y, Zeng K, Han Y, Wang L, Chen D, Xi Z, Wang H, Wang X, Chen G (2012) Altered expression of CX3CL1 in patients with epilepsy and in a rat model. Am J Pathol 180:1950–1962

    Article  CAS  PubMed  Google Scholar 

  • Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA (2007) Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab 27:697–709

    Article  CAS  PubMed  Google Scholar 

  • Yu FH, Mantegazza M, Westenbroek RE, Robbins CA, Kalume F, Burton KA, Spain WJ, McKnight GS, Scheuer T, Catterall WA (2006) Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nat Neurosci 9:1142–1149

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Dong H, Duan L, Yuan G, Liang W, Li Q, Zhang X, Pan Y (2019) SLC1A2 mediates refractory temporal lobe epilepsy with an initial precipitating injury by targeting the glutamatergic synapse pathway. IUBMB Life 71:213–222

    Article  CAS  PubMed  Google Scholar 

  • Minocycline- and tetracycline-class antibiotics are protective against partial seizures in vivoWang, Doris D. et al.Epilepsy & Behavior, Volume 24, Issue 3, 314 - 318

    Google Scholar 

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Acknowledgement

This work was supported by the Magnetoencephalography (MEG) Resource Facility grant funded by Department of Biotechnology, Ministry of Science & Technology, Govt. of India [Grant: BT/MED/122/SP24580/2018].

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Authors and Affiliations

  1. Department of Neurosurgery, All India Institute of Medical Sciences (AIIMS), New Delhi, India

    Aastha Dheer & P. Sarat Chandra

  2. Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, New Delhi, India

    Aparna Banerjee Dixit

  3. Department of Neurology, All India Institute of Medical Sciences (AIIMS), New Delhi, India

    Manjari Tripathi

  4. Department of Biophysics, All India Institute of Medical Sciences (AIIMS), New Delhi, India

    Jyotirmoy Banerjee

Authors
  1. Aastha Dheer
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  2. Aparna Banerjee Dixit
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  3. Manjari Tripathi
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  4. P. Sarat Chandra
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  5. Jyotirmoy Banerjee
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Corresponding author

Correspondence to Jyotirmoy Banerjee .

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Editors and Affiliations

  1. School of Studies in Neuroscience, Jiwaji University, Gwalior, Madhya Pradesh, India

    Ishan Patro

  2. Cellular and Molecular Neurosciences, National Brain Research Centre, Manesar, Haryana, India

    Pankaj Seth

  3. School of Studies in Neuroscience, Jiwaji University, Gwalior, Madhya Pradesh, India

    Nisha Patro

  4. National Brain Research Centre, Manesar, Haryana, India

    Prakash Narain Tandon

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Dheer, A., Dixit, A.B., Tripathi, M., Chandra, P.S., Banerjee, J. (2022). Glia in Epilepsy: An Overview. In: Patro, I., Seth, P., Patro, N., Tandon, P.N. (eds) The Biology of Glial Cells: Recent Advances. Springer, Singapore. https://doi.org/10.1007/978-981-16-8313-8_12

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