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Crucial Role for Astrocytes in Epilepsy

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Pathological Potential of Neuroglia

Abstract

Epilepsy is characterized by the periodic occurrence of seizures. Currently available anticonvulsant drugs and therapies are insufficient to controlling seizures in about one third of patients. Thus, there is an urgent need for new therapies that prevent generation of the disorder and improve seizure control in individuals already afflicted. The vast majority of epileptic cases are of idiopathic origin with their underlying mechanisms being unclear. Neurosurgical specimens from patients presenting with mesial temporal lobe epilepsy (MTLE) demonstrate marked reactive gliosis. Since recent studies have implicated astrocytes in important physiological roles in the central nervous system, such as synchronization of neuronal firing, it is plausible they may also have a role in seizure generation and/or seizure spread. In support of this view, various membrane channels, receptors and transporters in astrocytic membranes are altered in the epileptic brain. Excitingly, recent evidence suggests that in the course of the pathogenesis of MTLE, these glial changes alter homeostatic network functions and temporally precede the alterations in neurons. These findings might eventually classify MTLE as a glial rather than a neuronal disorder, and identify astrocytes as promising new targets for the development of more specific antiepileptic therapeutic strategies.

This chapter summarizes current evidence of astrocyte dysfunction in epilepsy and discusses presumed underlying mechanisms. Although research on astrocytes in epilepsy is still in its infancy, the review clearly demonstrate a critical role of astrocytes in the disturbance of K+ and transmitter homeostasis and its impact on seizure generation.

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References

  • Aden U, O’Connor WT, Berman RF (2004) Changes in purine levels and adenosine receptors in kindled seizures in the rat. Neuroreport 15:1585–1589

    PubMed  CAS  Google Scholar 

  • Akbar MT, Torp R, Danbolt NC, Levy LM, Meldrum BS, Ottersen OP (1997) Expression of glial glutamate transporters GLT-1 and GLAST is unchanged in the hippocampus in fully kindled rats. Neuroscience 78:351–359

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Angulo MC, Kozlov AS, Charpak S, Audinat E (2004) Glutamate released from glial cells synchronizes neuronal activity in the hippocampus. J Neurosci 24:6920–6927

    PubMed  CAS  Google Scholar 

  • Aronica E, Van Vliet EA, Mayboroda OA, Troost D, Da Silva FHL, 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

    PubMed  CAS  Google Scholar 

  • Aronica E, Gorter JA, Jansen GH, Leenstra S, Yankaya B, Troost D (2001) Expression of connexin 43 and connexin 32 gap-junction proteins in epilepsy-associated brain tumors and in the perilesional epileptic cortex. Acta Neuropathol 101:449–459

    PubMed  CAS  Google Scholar 

  • Aronica E, Zurolo E, Iyer A, de GM, 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

    Google Scholar 

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

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Ault B, Olney MA, Joyner JL, Boyer CE, Notrica MA, Soroko FE, Wang CM (1987) Pro-convulsant actions of theophylline and caffeine in the hippocampus: implications for the management of temporal lobe epilepsy. Brain Res 426:93–102

    PubMed  CAS  Google Scholar 

  • Auvin S, Porta N, Nehlig A, Lecointe C, Vallee L, Bordet R (2009) Inflammation in rat pups subjected to short hyperthermic seizures enhances brain long-term excitability. Epilepsy Res 86:124–130

    PubMed  CAS  Google Scholar 

  • Auvin S, Shin D, Mazarati A, Sankar R (2010) Inflammation induced by LPS enhances epileptogenesis in immature rat and may be partially reversed by IL1RA. Epilepsia 51(Suppl 3):34–38

    PubMed  CAS  PubMed Central  Google Scholar 

  • Avsar E, Empson RM (2004) Adenosine acting via A1 receptors, controls the transition to status epilepticus-like behaviour in an in vitro model of epilepsy. Neuropharmacology 47:427–437

    PubMed  CAS  Google Scholar 

  • Balestrino M, Somjen GG (1986) Chlorpromazine protects brain tissue in hypoxia by delaying spreading depression-mediated calcium influx. Brain Res 385:219–226

    PubMed  CAS  Google Scholar 

  • Barraco RA, Swanson TH, Phillis JW, Berman RF (1984) Anticonvulsant effects of adenosine analogues on amygdaloid-kindled seizures in rats. Neurosci Lett 46:317–322

    PubMed  CAS  Google Scholar 

  • Bedner P, Steinhauser C (2013) Altered Kir and gap junction channels in temporal lobe epilepsy. Neurochem Int 63:682–687

    PubMed  CAS  Google Scholar 

  • Ben-Ari Y (1985) Limbic seizure and brain damage produced by kainic acid: mechanisms and relevance to human temporal lobe epilepsy. Neuroscience 14:375–403

    PubMed  CAS  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

    PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  • Binder DK, Oshio K, Ma T, Verkman AS, Manley GT (2004a) Increased seizure threshold in mice lacking aquaporin-4 water channels. Neuroreport 15:259–262

    CAS  Google Scholar 

  • Binder DK, Papadopoulos MC, Haggie PM, Verkman AS (2004b) In vivo measurement of brain extracellular space diffusion by cortical surface photobleaching. J Neurosci 24:8049–8056

    CAS  Google Scholar 

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

    PubMed  Google Scholar 

  • Bockenhauer D et al (2009) Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations. N Engl J Med 360:1960–1970

    PubMed  CAS  PubMed Central  Google Scholar 

  • Boison D (2010) Adenosine dysfunction and adenosine kinase in epileptogenesis. Open Neurosci J 4:93–101

    PubMed  CAS  PubMed Central  Google Scholar 

  • Boison D (2012) Adenosine dysfunction in epilepsy. Glia 60:1234–1243

    PubMed  PubMed Central  Google Scholar 

  • Boison D, Scheurer L, Tseng JL, Aebischer P, Mohler H (1999) Seizure suppression in kindled rats by intraventricular grafting of an adenosine releasing synthetic polymer. Exp Neurol 160:164–174

    PubMed  CAS  Google Scholar 

  • Boison D, Huber A, Padrun V, Deglon N, Aebischer P, Mohler H (2002) Seizure suppression by adenosine-releasing cells is independent of seizure frequency. Epilepsia 43:788–796

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Bostanci MO, Bagirici F (2006) The effects of octanol on penicillin induced epileptiform activity in rats: an in vivo study. Epilepsy Res 71:188–194

    PubMed  CAS  Google Scholar 

  • Bostanci MO, Bagirici F (2007) Anticonvulsive effects of carbenoxolone on penicillin-induced epileptiform activity: an in vivo study. Neuropharmacology 52:362–367

    PubMed  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

    PubMed  CAS  Google Scholar 

  • Campbell SL, Hablitz JJ (2004) Glutamate transporters regulate excitability in local networks in rat neocortex. Neuroscience 127:625–635

    PubMed  CAS  Google Scholar 

  • Carlen PL (2012) Curious and contradictory roles of glial connexins and pannexins in epilepsy. Brain Res 1487:54–60

    PubMed  CAS  Google Scholar 

  • Cavus I, Kasoff WS, Cassaday MP, Jacob R, Gueorguieva R, Sherwin RS, Krystal JH, Spencer DD, bi-Saab WM (2005) Extracellular metabolites in the cortex and hippocampus of epileptic patients. Ann Neurol 57:226–235

    PubMed  CAS  Google Scholar 

  • Charles AC, Merrill JE, Dirksen ER, Sanderson MJ (1991) Intercellular signaling in glial cells: calcium waves and oscillations in response to mechanical stimulation and glutamate. Neuron 6:983–992

    PubMed  CAS  Google Scholar 

  • Chebabo SR, Hester MA, Aitken PG, Somjen GG (1995) Hypotonic exposure enhances synaptic transmission and triggers spreading depression in rat hippocampal tissue slices. Brain Res 695:203–216

    PubMed  CAS  Google Scholar 

  • Chever O, Djukic B, McCarthy KD, Amzica F (2010) Implication of kir4.1 channel in excess potassium clearance: an in vivo study on anesthetized glial-conditional kir4.1 knock-out mice. J Neurosci 30:15769–15777

    PubMed  CAS  Google Scholar 

  • Collignon F, Wetjen NM, Cohen-Gadol AA, Cascino GD, Parisi J, Meyer FB, Marsh WR, Roche P, Weigand SD (2006) Altered expression of connexin subtypes in mesial temporal lobe epilepsy in humans. J Neurosurg 105:77–87

    PubMed  CAS  Google Scholar 

  • Condorelli DF, Mudo G, Trovato-Salinaro A, Mirone MB, Amato G, Belluardo N (2002) Connexin-30 mRNA is up-regulated in astrocytes and expressed in apoptotic neuronal cells of rat brain following kainate-induced seizures. Mol Cell Neurosci 21:94–113

    PubMed  CAS  Google Scholar 

  • Cornell-Bell AH, Finkbeiner SM, Cooper MS, Smith SJ (1990) Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling. Science 247:470–473

    PubMed  CAS  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  • Cremer CM, Palomero-Gallagher N, Bidmon HJ, Schleicher A, Speckmann EJ, Zilles K (2009) Pentylenetetrazole-induced seizures affect binding site densities for GABA, glutamate and adenosine receptors in the rat brain. Neuroscience 163:490–499

    PubMed  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

    PubMed  CAS  Google Scholar 

  • Crunelli V, Carmignoto G (2013) New vistas on astroglia in convulsive and non-convulsive epilepsy highlight novel astrocytic targets for treatment. J Physiol 591:775–785

    PubMed  CAS  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

  • Das A, Wallace GC, Holmes C, McDowell ML, Smith JA, Marshall JD, Bonilha L, Edwards JC, Glazier SS, Ray SK, Banik NL (2012) Hippocampal tissue of patients with refractory temporal lobe epilepsy is associated with astrocyte activation, inflammation, and altered expression of channels and receptors. Neuroscience 220:237–246

    PubMed  CAS  PubMed Central  Google Scholar 

  • David Y, Cacheaux LP, Ivens S, Lapilover E, Heinemann U, Kaufer D, Friedman A (2009) Astrocytic dysfunction in epileptogenesis: consequence of altered potassium and glutamate homeostasis? J Neurosci 29:10588–10599

    PubMed  CAS  PubMed Central  Google Scholar 

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

    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

    PubMed  CAS  PubMed Central  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

    PubMed  CAS  Google Scholar 

  • Dragunow M, Goddard GV, Laverty R (1985) Is adenosine an endogenous anticonvulsant? Epilepsia 26:480–487

    PubMed  CAS  Google Scholar 

  • Dube CM, McClelland S, Choy MK, Brewster AL, Noam Y, Baram TZ (2012) Fever, febrile seizures and epileptogenesis. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV (eds) Jasper’s basic mechanisms of the epilepsies. Oxford University, Betheseda, pp 343–352

    Google Scholar 

  • Dudek FE, Obenaus A, Tasker JG (1990) Osmolality-induced changes in extracellular volume alter epileptiform bursts independent of chemical synapses in the rat: importance of non-synaptic mechanisms in hippocampal epileptogenesis. Neurosci Lett 120:267–270

    PubMed  CAS  Google Scholar 

  • Dunwiddie TV (1980) Endogenously released adenosine regulates excitability in the in vitro hippocampus. Epilepsia 21:541–548

    PubMed  CAS  Google Scholar 

  • Dunwiddie TV (1990) Electrophysiological aspects of adenosine receptor function. Adenosine Adenosine Recep 5:143–172

    Google Scholar 

  • Dunwiddie TV, Worth T (1982) Sedative and anticonvulsant effects of adenosine analogs in mouse and rat. J Pharmacol Exp Ther 220:70–76

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Eid T, Thomas MJ, Spencer DD, Runden-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 363:28–37

    PubMed  CAS  Google Scholar 

  • Eid T, Lee TS, Thomas MJ, Amiry-Moghaddam M, Bjornsen LP, Spencer DD, Agre P, Ottersen OP, De Lanerolle NC (2005) Loss of perivascular aquaporin 4 may underlie deficient water and K+ homeostasis in the human epileptogenic hippocampus. Proc Natl Acad Sci U S A 102:1193–1198

    PubMed  CAS  PubMed Central  Google Scholar 

  • Eid T, Ghosh A, Wang Y, Beckstrom 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

    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

    CAS  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 (2013a) Gene expression of glutamate metabolizing enzymes in the hippocampal formation in human temporal lobe epilepsy. Epilepsia 54:228–238

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  • Elisevich K, Rempel SA, Smith B, Allar N (1997a) Connexin 43 mRNA expression in two experimental models of epilepsy. Mol Chem Neuropathol 32:75–88

    CAS  Google Scholar 

  • Elisevich K, Rempel SA, Smith BJ, Edvardsen K (1997b) Hippocampal connexin 43 expression in human complex partial seizure disorder. Exp Neurol 145:154–164

    CAS  Google Scholar 

  • Elisevich K, Rempel SA, Smith B, Hirst K (1998) Temporal profile of connexin 43 mRNA expression in a tetanus toxin-induced seizure disorder. Mol Chem Neuropathol 35:23–37

    PubMed  CAS  Google Scholar 

  • Fedele DE, Li T, Lan JQ, Fredholm BB, Boison D (2006) Adenosine A1 receptors are crucial in keeping an epileptic focus localized. Exp Neurol 200:184–190

    PubMed  CAS  Google Scholar 

  • Fellin T, Pascual O, Gobbo S, Pozzan T, Haydon PG, Carmignoto G (2004) Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron 43:729–743

    PubMed  CAS  Google Scholar 

  • Fellin T, Gomez-Gonzalo M, Gobbo S, Carmignoto G, Haydon PG (2006) Astrocytic glutamate is not necessary for the generation of epileptiform neuronal activity in hippocampal slices. J Neurosci 26:9312–9322

    PubMed  CAS  Google Scholar 

  • Fisher RS, Pedley TA, Moody WJ Jr, Prince DA (1976) The role of extracellular potassium in hippocampal epilepsy. Arch Neurol 33:76–83

    PubMed  CAS  Google Scholar 

  • Fonseca CG, Green CR, Nicholson LF (2002) Upregulation in astrocytic connexin 43 gap junction levels may exacerbate generalized seizures in mesial temporal lobe epilepsy. Brain Res 929:105–116

    PubMed  CAS  Google Scholar 

  • Fredholm BB, Chen JF, Cunha RA, Svenningsson P, Vaugeois JM (2005) Adenosine and brain function. Int Rev Neurobiol 63:191–270

    PubMed  CAS  Google Scholar 

  • Fremeau RT Jr, Burman J, Qureshi T, Tran CH, Proctor J, Johnson J, Zhang H, Sulzer D, Copenhagen DR, Storm-Mathisen J, Reimer RJ, Chaudhry FA, Edwards RH (2002) The identification of vesicular glutamate transporter 3 suggests novel modes of signaling by glutamate. Proc Natl Acad Sci U S A 99:14488–14493

    PubMed  CAS  PubMed Central  Google Scholar 

  • Gajda Z, Gyengesi E, Hermesz E, Ali KS, Szente M (2003) Involvement of gap junctions in the manifestation and control of the duration of seizures in rats in vivo. Epilepsia 44:1596–1600

    PubMed  CAS  Google Scholar 

  • Galic MA, Riazi K, Heida JG, Mouihate A, Fournier NM, Spencer SJ, Kalynchuk LE, Teskey GC, Pittman QJ (2008) Postnatal inflammation increases seizure susceptibility in adult rats. J Neurosci 28:6904–6913

    PubMed  CAS  PubMed Central  Google Scholar 

  • Giaume C, Tabernero A, Medina JM (1997) Metabolic trafficking through astrocytic gap junctions. Glia 21:114–123

    PubMed  CAS  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

    PubMed  CAS  Google Scholar 

  • Gigout S, Louvel J, Kawasaki H, D’Antuono M, Armand V, Kurcewicz I, Olivier A, Laschet J, Turak B, Devaux B, Pumain R, Avoli M (2006) Effects of gap junction blockers on human neocortical synchronization. Neurobiol Dis 22:496–508

    PubMed  CAS  Google Scholar 

  • Glass M, Faull RLM, Bullock JY, Jansen K, Mee EW, Walker EB, Synek BJL, Dragunow M (1996) Loss of A1 adenosine receptors in human temporal lobe epilepsy. Brain Res 710:56–68

    PubMed  CAS  Google Scholar 

  • Gomez-Gonzalo M, Losi G, Chiavegato A, Zonta M, Cammarota M, Brondi M, Vetri F, Uva L, Pozzan T, De Curtis M, Ratto GM, Carmignoto G (2010) An excitatory loop with astrocytes contributes to drive neurons to seizure threshold. PLoS Biol 8:e1000352

    PubMed  PubMed Central  Google Scholar 

  • Gordon GR, Baimoukhametova DV, Hewitt SA, Rajapaksha WR, Fisher TE, Bains JS (2005) Norepinephrine triggers release of glial ATP to increase postsynaptic efficacy. Nat Neurosci 8:1078–1086

    PubMed  CAS  Google Scholar 

  • Gouder N, Fritschy JM, Boison D (2003) Seizure suppression by adenosine A1 receptor activation in a mouse model of pharmacoresistant epilepsy. Epilepsia 44:877–885

    PubMed  CAS  Google Scholar 

  • Gouder N, Scheurer L, Fritschy JM, Boison D (2004) Overexpression of adenosine kinase in epileptic hippocampus contributes to epileptogenesis. J Neurosci 24:692–701

    PubMed  CAS  Google Scholar 

  • Guo F, Sun F, Yu JL, Wang QH, Tu DY, Mao XY, Liu R, Wu KC, Xie N, Hao LY, Cai JQ (2010) Abnormal expressions of glutamate transporters and metabotropic glutamate receptor 1 in the spontaneously epileptic rat hippocampus. Brain Res Bull 81:510–516

    PubMed  CAS  Google Scholar 

  • Haberle J, Gorg B, Rutsch F, Schmidt E, Toutain A, Benoist JF, Gelot A, Suc AL, Hohne W, Schliess F, Haussinger D, Koch HG (2005) Congenital glutamine deficiency with glutamine synthetase mutations. N Engl J Med 353:1926–1933

    PubMed  Google Scholar 

  • Haberle J, Gorg B, Toutain A, Rutsch F, Benoist JF, Gelot A, Suc AL, Koch HG, Schliess F, Haussinger D (2006) Inborn error of amino acid synthesis: human glutamine synthetase deficiency. J Inherit Metab Dis 29:352–358

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  • Haghikia A, Ladage K, Hinkerohe D, Vollmar P, Heupel K, Dermietzel R, Faustmann PM (2008) Implications of antiinflammatory properties of the anticonvulsant drug levetiracetam in astrocytes. J Neurosci Res 86:1781–1788

    PubMed  CAS  Google Scholar 

  • Haglund MM, Hochman DW (2005) Furosemide and mannitol suppression of epileptic activity in the human brain. J Neurophysiol 94:907–918

    PubMed  CAS  Google Scholar 

  • Haj-Yasein NN, Jensen V, Vindedal GF, Gundersen GA, Klungland A, Ottersen OP, Hvalby O, Nagelhus EA (2011) Evidence that compromised K(+) spatial buffering contributes to the epileptogenic effect of mutations in the human kir4.1 gene (KCNJ10). Glia 59:1635–1642

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Hammer J, Alvestad S, Osen KK, Skare O, Sonnewald U, Ottersen OP (2008) Expression of glutamine synthetase and glutamate dehydrogenase in the latent phase and chronic phase in the kainate model of temporal lobe epilepsy. Glia 56:856–868

    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

    PubMed  CAS  Google Scholar 

  • Heinemann U, Gabriel S, Jauch R, Schulze K, Kivi A, Eilers A, Kovacs R, Lehmann TN (2000) Alterations of glial cell function in temporal lobe epilepsy. Epilepsia 41:S185–S189

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Heuser K, Eid T, Lauritzen F, Thoren AE, Vindedal GF, Tauboll 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

    PubMed  CAS  PubMed Central  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Hu S, Sheng WS, Ehrlich LC, Peterson PK, Chao CC (2000) Cytokine effects on glutamate uptake by human astrocytes. Neuroimmunomodulation 7:153–159

    PubMed  CAS  Google Scholar 

  • Huber A, Padrun V, Deglon N, Aebischer P, Möhler H, Boison D (2001) Grafts of adenosine-releasing cells suppress seizures in kindling epilepsy. Proc Natl Acad Sci U S A 98:7611–7616

    PubMed  CAS  PubMed Central  Google Scholar 

  • Jahromi SS, Wentlandt K, Piran S, Carlen PL (2002) Anticonvulsant actions of gap junctional blockers in an in vitro seizure model. J Neurophysiol 88:1893–1902

    PubMed  CAS  Google Scholar 

  • Jauch R, Windmuller O, Lehmann TN, Heinemann U, Gabriel S (2002) 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 925:18–27

    PubMed  CAS  Google Scholar 

  • Jin BJ, Zhang H, Binder DK, Verkman AS (2013) Aquaporin-4-dependent K(+) and water transport modeled in brain extracellular space following neuroexcitation. J Gen Physiol 141:119–132

    PubMed  CAS  PubMed Central  Google Scholar 

  • Kam K, Nicoll R (2007) Excitatory synaptic transmission persists independently of the glutamate-glutamine cycle. J Neurosci 27:9192–9200

    PubMed  CAS  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 23:1212–1220

    PubMed  CAS  Google Scholar 

  • Kang J, Kang N, Lovatt D, Torres A, Zhao Z, Lin J, Nedergaard M (2008) Connexin 43 hemichannels are permeable to ATP. J Neurosci 28:4702–4711

    PubMed  CAS  PubMed Central  Google Scholar 

  • Khurgel M, Ivy GO (1996) Astrocytes in kindling: relevance to epileptogenesis. Epilepsy Res 26:163–175

    PubMed  CAS  Google Scholar 

  • Kivi A, Lehmann TN, Kovacs R, Eilers A, Jauch R, Meencke HJ, Von Deimling A, Heinemann U, Gabriel S (2000) Effects of barium on stimulus-induced rises of [K+]o in human epileptic non-sclerotic and sclerotic hippocampal area CA1. Eur J Neurosci 12:2039–2048

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  PubMed Central  Google Scholar 

  • Kofuji P, Ceelen P, Zahs KR, Surbeck LW, Lester HA, Newman EA (2000) Genetic inactivation of an inwardly rectifying potassium channel (Kir4.1 subunit) in mice: phenotypic impact in retina. J Neurosci 20:5733–5740

    PubMed  CAS  PubMed Central  Google Scholar 

  • Kohling R, Gladwell SJ, Bracci E, Vreugdenhil M, Jefferys JG (2001) Prolonged epileptiform bursting induced by 0-Mg(2+) in rat hippocampal slices depends on gap junctional coupling. Neuroscience 105:579–587

    PubMed  CAS  Google Scholar 

  • Kowaluk EA, Jarvis MF (2000) Therapeutic potential of adenosine kinase inhibitors. Expert Opin Investig Drugs 9:551–564

    PubMed  CAS  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

    PubMed  CAS  Google Scholar 

  • Kumaria A, Tolias CM, Burnstock G (2008) ATP signalling in epilepsy. Purinergic Signal 4:339–346

    PubMed  CAS  PubMed Central  Google Scholar 

  • Kunze A, Congreso MR, Hartmann C, Wallraff-Beck A, Hüttmann K, Bedner P, Requardt R, Seifert G, Redecker C, Willecke K, Hofmann A, Pfeifer A, Theis M, Steinhäuser C (2009) Connexin expression by radial glia-like cells is required for neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci U S A 106:11336–11341

    PubMed  CAS  PubMed Central  Google Scholar 

  • Lee KS, Schubert P, Heinemann U (1984) The anticonvulsive action of adenosine: a postsynaptic, dendritic action by a possible endogenous anticonvulsant. Brain Res 321:160–164

    PubMed  CAS  Google Scholar 

  • Lee SH, Magge S, Spencer DD, Sontheimer H, Cornell-Bell AH (1995) Human epileptic astrocytes exhibit increased gap junction coupling. Glia 15:195–202

    PubMed  CAS  Google Scholar 

  • Lee TS, Eid T, Mane S, Kim JH, Spencer DD, Ottersen OP, De Lanerolle NC (2004) Aquaporin-4 is increased in the sclerotic hippocampus in human temporal lobe epilepsy. Acta Neuropathol 108:493–502

    PubMed  CAS  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

    PubMed  CAS  PubMed Central  Google Scholar 

  • Li J, Shen H, Naus CC, Zhang L, Carlen PL (2001) Upregulation of gap junction connexin 32 with epileptiform activity in the isolated mouse hippocampus. Neuroscience 105:589–598

    PubMed  CAS  Google Scholar 

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

    Google Scholar 

  • Li T, Steinbeck JA, Lusardi T, Koch P, Lan JQ, Wilz A, Segschneider M, Simon RP, Brustle O, Boison D (2007b) Suppression of kindling epileptogenesis by adenosine releasing stem cell-derived brain implants. Brain 130:1276–1288

    Google Scholar 

  • Li T, Ren G, Lusardi T, Wilz A, Lan JQ, Iwasato T, Itohara S, Simon RP, Boison D (2008) Adenosine kinase is a target for the prediction and prevention of epileptogenesis in mice. J Clin Invest 118:571–582

    PubMed  CAS  PubMed Central  Google Scholar 

  • Li T, Lytle N, Lan JQ, Sandau US, Boison D (2012) Local disruption of glial adenosine homeostasis in mice associates with focal electrographic seizures: a first step in epileptogenesis? Glia 60:83–95

    PubMed  PubMed Central  Google Scholar 

  • Li M, Kang R, Shi J, Liu G, Zhang J (2013) Anticonvulsant activity of b2, an adenosine analog, on chemical convulsant-induced seizures. PLoS ONE 8:e67060

    PubMed  CAS  PubMed Central  Google Scholar 

  • Liang SL, Carlson GC, Coulter DA (2006) Dynamic regulation of synaptic GABA release by the glutamate-glutamine cycle in hippocampal area CA1. J Neurosci 26:8537–8548

    PubMed  CAS  PubMed Central  Google Scholar 

  • Lopes MW, Soares FM, de MN, Nunes JC, Cajado AG, de BD, de Cordova FM, da Cunha RM, Walz R, Leal RB (2013) Time-dependent modulation of AMPA receptor phosphorylation and mRNA expression of NMDA receptors and glial glutamate transporters in the rat hippocampus and cerebral cortex in a pilocarpine model of epilepsy. Exp Brain Res 226:153–163

    Google Scholar 

  • Losi G, Cammarota M, Chiavegato A, Gomez-Gonzalo M, Carmignoto G (2010) A new experimental model of focal seizures in the entorhinal cortex. Epilepsia 51:1493–1502

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Maroso M, Balosso S, Ravizza T, Liu J, Aronica E, Iyer AM, Rossetti C, Molteni M, Casalgrandi M, Manfredi AA, Bianchi ME, Vezzani A (2010) Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nat Med 16:413–419

    PubMed  CAS  Google Scholar 

  • Maroso M, Balosso S, Ravizza T, Liu J, Bianchi ME, Vezzani A (2011) Interleukin-1 type 1 receptor/Toll-like receptor signalling in epilepsy: the importance of IL-1beta and high-mobility group box 1. J Intern Med 270:319–326

    PubMed  CAS  Google Scholar 

  • Mathern GW, Mendoza D, Lozada A, Pretorius JK, Dehnes Y, Danbolt NC, Nelson N, Leite JP, Chimelli L (1999) Hippocampal GABA and glutamate transporter immunoreactivity in patients with temporal lobe epilepsy. Neurology 52:453–472

    PubMed  CAS  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

    PubMed  CAS  Google Scholar 

  • Medina-Ceja L, Cordero-Romero A, Morales-Villagran A (2008) Antiepileptic effect of carbenoxolone on seizures induced by 4-aminopyridine: a study in the rat hippocampus and entorhinal cortex. Brain Res 1187:74–81

    PubMed  CAS  Google Scholar 

  • Meme W, Calvo CF, Froger N, Ezan P, Amigou E, Koulakoff A, Giaume C (2006) Proinflammatory cytokines released from microglia inhibit gap junctions in astrocytes: potentiation by beta-amyloid. FASEB J 20:494–496

    PubMed  CAS  Google Scholar 

  • Miller HP, Levey AI, Rothstein JD, Tzingounis AV, Conn PJ (1997) Alterations in glutamate transporter protein levels in kindling- induced epilepsy. J Neurochem 68:1564–1570

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Mylvaganam S, Zhang L, Wu C, Zhang ZJ, Samoilova M, Eubanks J, Carlen PL, Poulter MO (2010) Hippocampal seizures alter the expression of the pannexin and connexin transcriptome. J Neurochem 112:92–102

    PubMed  CAS  Google Scholar 

  • Nadler JV, Cuthbertson GJ (1980) Kainic acid neurotoxicity toward hippocampal formation: dependence on specific excitatory pathways. Brain Res 195:47–56

    PubMed  CAS  Google Scholar 

  • Nagelhus EA, Horio Y, Inanobe A, Fujita A, Haug FM, Nielsen S, Kurachi Y, Ottersen OP (1999) Immunogold evidence suggests that coupling of K+ siphoning and water transport in rat retinal Muller cells is mediated by a coenrichment of Kir4.1 and AQP4 in specific membrane domains. Glia 26:47–54

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Naus CCG, Bechberger JF, Paul DL (1991) Gap junction gene expression in human seizure disorder. Exp Neurol 111:198–203

    PubMed  CAS  Google Scholar 

  • Navarrete M, Perea G, Maglio L, Pastor J, Garcia de SR, Araque A (2013) Astrocyte calcium signal and gliotransmission in human brain tissue. Cereb Cortex 23:1240–1246

    PubMed  Google Scholar 

  • Nemani VM, Binder DK (2005) Emerging role of gap junctions in epilepsy. Histol Histopathol 20:253–259

    PubMed  CAS  Google Scholar 

  • Neusch C, Rozengurt N, Jacobs RE, Lester HA, Kofuji P (2001) Kir4.1 potassium channel subunit is crucial for oligodendrocyte development and in vivo myelination. J Neurosci 21:5429–5438

    PubMed  CAS  Google Scholar 

  • Olney JW, Sharpe LG, Feigin RD (1972) Glutamate-induced brain damage in infant primates. J Neuropathol Exp Neurol 31:464–488

    PubMed  CAS  Google Scholar 

  • Orellana JA, Saez PJ, Shoji KF, Schalper KA, Palacios-Prado N, Velarde V, Giaume C, Bennett MVL, Saez JC (2009) Modulation of brain hemichannels and gap junction channels by pro-inflammatory agents and their possible role in neurodegeneration. Antioxid Redox Signal 11:369–399

    PubMed  CAS  PubMed Central  Google Scholar 

  • Orellana JA, Martinez AD, Retamal MA (2013) Gap junction channels and hemichannels in the CNS: regulation by signaling molecules. Neuropharmacology 75:567–582

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  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

    PubMed  CAS  PubMed Central  Google Scholar 

  • Padmawar P, Yao X, Bloch O, Manley GT, Verkman AS (2005) K+ waves in brain cortex visualized using a long-wavelength K+-sensing fluorescent indicator. Nat Methods 2:825–827

    PubMed  CAS  Google Scholar 

  • Pan E, Stringer JL (1996) Influence of osmolality on seizure amplitude and propagation in the rat dentate gyrus. Neurosci Lett 207:9–12

    PubMed  CAS  Google Scholar 

  • Pannasch U, Rouach N (2013) Emerging role for astroglial networks in information processing: from synapse to behavior. Trends Neurosci 36:405–417

    PubMed  CAS  Google Scholar 

  • Pannasch U, Vargova L, Reingruber J, Ezan P, Holcman D, Giaume C, Sykova E, Rouach N (2011) Astroglial networks scale synaptic activity and plasticity. Proc Natl Acad Sci U S A 108:8467–8472

    PubMed  CAS  PubMed Central  Google Scholar 

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

    PubMed  CAS  PubMed Central  Google Scholar 

  • Pascual O, Casper KB, Kubera C, Zhang J, Revilla-Sanchez R, Sul JY, Takano H, Moss SJ, McCarthy K, Haydon PG (2005a) Astrocytic purinergic signaling coordinates synaptic networks. Science 310:113–116

    CAS  Google Scholar 

  • Pascual O, Casper KB, Kubera C, Zhang J, Revilla-Sanchez R, Sul JY, Takano H, Moss SJ, McCarthy K, Haydon PG (2005b) Astrocytic purinergic signaling coordinates synaptic networks. Science 310:113–116

    CAS  Google Scholar 

  • Perez EL, Lauritzen F, Wang Y, Lee TS, Kang D, Zaveri HP, Chaudhry FA, Ottersen OP, Bergersen LH, Eid T (2012) Evidence for astrocytes as a potential source of the glutamate excess in temporal lobe epilepsy. Neurobiol Dis 47:331–337

    PubMed  CAS  PubMed Central  Google Scholar 

  • Perez-Velazquez JL, Valiante TA, Carlen PL (1994) Modulation of gap junctional mechanisms during calcium-free induced field burst activity: a possible role for electrotonic coupling in epileptogenesis. J Neurosci 14:4308–4317

    PubMed  CAS  Google Scholar 

  • Petroff OA, Errante LD, Kim JH, Spencer DD (2003) N-acetyl-aspartate, total creatine, and myo-inositol in the epileptogenic human hippocampus. Neurology 60:1646–1651

    PubMed  CAS  Google Scholar 

  • Porter JT, McCarthy KD (1996) Hippocampal astrocytes in situ respond to glutamate released from synaptic terminals. J Neurosci 16:5073–5081

    PubMed  CAS  Google Scholar 

  • Proper EA, Hoogland G, Kappen SM, Jansen GH, Rensen MG, Schrama LH, van Veelen CW, van Rijen PC, van Nieuwenhuizen O, Gispen WH, De Graan PN (2002) Distribution of glutamate transporters in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy. Brain 125:32–43

    PubMed  CAS  Google Scholar 

  • Ransom CB, Sontheimer H (1995) Biophysical and pharmacological characterization of inwardly rectifying K+ currents in rat spinal cord astrocytes. J Neurophysiol 73:333–346

    PubMed  CAS  Google Scholar 

  • Ransom CB, Ransom BR, Sontheimer H (2000) Activity-dependent extracellular K+ accumulation in rat optic nerve: the role of glial and axonal Na+ pumps. J Physiol (Lond) 522:427–442

    CAS  Google Scholar 

  • Ravizza T, Gagliardi B, Noe 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

    PubMed  CAS  Google Scholar 

  • Reichold M, Zdebik AA, Lieberer E, Rapedius M, Schmidt K, Bandulik S, Sterner C, Tegtmeier I, Penton D, Baukrowitz T, Hulton SA, Witzgall R, Ben-Zeev B, Howie AJ, Kleta R, Bockenhauer D, Warth R (2010) KCNJ10 gene mutations causing EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function. Proc Natl Acad Sci U S A 107:14490–14495

    PubMed  CAS  PubMed Central  Google Scholar 

  • Retamal MA, Froger N, Palacios-Prado N, Ezan P, Saez PJ, Saez JC, Giaume C (2007) Cx43 hemichannels and gap junction channels in astrocytes are regulated oppositely by proinflammatory cytokines released from activated microglia. J Neurosci 27:13781–13792

    PubMed  CAS  Google Scholar 

  • Roper SN, Obenaus A, Dudek FE (1992) Osmolality and nonsynaptic epileptiform bursts in rat CA1 and dentate gyrus. Ann Neurol 31:81–85

    PubMed  CAS  Google Scholar 

  • Ross FM, Gwyn P, Spanswick D, Davies SN (2000) Carbenoxolone depresses spontaneous epileptiform activity in the CA1 region of rat hippocampal slices. Neuroscience 100:789–796

    PubMed  CAS  Google Scholar 

  • Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW, Kanai Y, Hediger MA, Wang YF, Schielke JP, Welty DF (1996) Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16:675–686

    PubMed  CAS  Google Scholar 

  • Rouach N, Koulakoff A, Abudara V, Willecke K, Giaume C (2008) Astroglial metabolic networks sustain hippocampal synaptic transmission. Science 322:1551–1555

    PubMed  CAS  Google Scholar 

  • Ruiz-Ederra J, Zhang H, Verkman AS (2007) Evidence against functional interaction between aquaporin-4 water channels and Kir4.1 K+ channels in retinal muller cells. J Biol Chem 282:21866–21872

    PubMed  CAS  Google Scholar 

  • Samoilova M, Li J, Pelletier MR, Wentlandt K, Adamchik Y, Naus CC, Carlen PL (2003) Epileptiform activity in hippocampal slice cultures exposed chronically to bicuculline: increased gap junctional function and expression. J Neurochem 86:687–699

    PubMed  CAS  Google Scholar 

  • Samoilova M, Wentlandt K, Adamchik Y, Velumian AA, Carlen PL (2008) Connexin 43 mimetic peptides inhibit spontaneous epileptiform activity in organotypic hippocampal slice cultures. Exp Neurol 210:762–775

    PubMed  CAS  Google Scholar 

  • Santiago MF, Veliskova J, Patel NK, Lutz SE, Caille D, Charollais A, Meda P, Scemes E (2011) Targeting pannexin1 improves seizure outcome. PLoS ONE 6:e25178

    PubMed  CAS  PubMed Central  Google Scholar 

  • Scemes E, Giaume C (2006) Astrocyte calcium waves: what they are and what they do. Glia 54:716–725

    PubMed  PubMed Central  Google Scholar 

  • Scemes E, Spray DC (1998) Increased intercellular communication in mouse astrocytes exposed to hyposmotic shocks. Glia 24:74–84

    PubMed  CAS  PubMed Central  Google Scholar 

  • Scemes E, Spray DC (2012) Extracellular K(+) and astrocyte signaling via connexin and pannexin channels Neurochem Res 37:2310–2316

    PubMed  CAS  PubMed Central  Google Scholar 

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

    PubMed  CAS  PubMed Central  Google Scholar 

  • Schröder W, Hinterkeuser S, Seifert G, Schramm J, Jabs R, Wilkin GP, Steinhäuser C (2000) Functional and molecular properties of human astrocytes in acute hippocampal slices obtained from patients with temporal lobe epilepsy. Epilepsia 41:S181–S184

    PubMed  Google Scholar 

  • Schwartzkroin PA, Baraban SC, Hochman DW (1998) Osmolarity, ionic flux, and changes in brain excitability. Epilepsy Res 32:275–285

    PubMed  CAS  Google Scholar 

  • Seifert G, Schilling K, Steinhäuser C (2006) Astrocyte dysfunction in neurological disorders: a molecular perspective. Nat Rev Neurosci 7:194–206

    PubMed  CAS  Google Scholar 

  • Seifert G, Hüttmann K, Binder DK, Hartmann C, Wyczynski A, Neusch C, Steinhäuser C (2009) Analysis of astroglial K+ channel expression in the developing hippocampus reveals a predominant role of the Kir4.1 subunit. J Neurosci 29:7474–7488

    PubMed  CAS  Google Scholar 

  • Sicca F, Imbrici P, D’Adamo MC, Moro F, Bonatti F, Brovedani P, Grottesi A, Guerrini R, Masi G, Santorelli FM, Pessia M (2011) Autism with seizures and intellectual disability: possible causative role of gain-of-function of the inwardly-rectifying K(+) channel Kir4.1. Neurobiol Dis 43:239–247

    PubMed  CAS  Google Scholar 

  • Simantov R, Crispino M, Hoe W, Broutman G, Tocco G, Rothstein JD, Baudry M (1999) Changes in expression of neuronal and glial glutamate transporters in rat hippocampus following kainate-induced seizure activity. Brain Res Mol Brain Res 65:112–123

    PubMed  CAS  Google Scholar 

  • Söhl G, Güldenagel M, Beck H, Teubner B, Traub O, Gutierrez R, Heinemann U, Willecke K (2000) Expression of connexin genes in hippocampus of kainate-treated and kindled rats under conditions of experimental epilepsy. Mol Brain Res 83:44–51

    PubMed  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

    PubMed  Google Scholar 

  • Strohschein S, Hüttmann K, Gabriel S, Binder DK, Heinemann U, Steinhäuser C (2011) Impact of aquaporin-4 channels on K(+) buffering and gap junction coupling in the hippocampus. Glia 59:973–980

    PubMed  Google Scholar 

  • Suadicani SO, Iglesias R, Wang J, Dahl G, Spray DC, Scemes E (2012) ATP signaling is deficient in cultured Pannexin1-null mouse astrocytes. Glia 60:1106–1116

    PubMed  PubMed Central  Google Scholar 

  • Szente M, Gajda Z, Said AK, Hermesz E (2002) Involvement of electrical coupling in the in vivo ictal epileptiform activity induced by 4-aminopyridine in the neocortex. Neuroscience 115:1067–1078

    PubMed  CAS  Google Scholar 

  • Takahashi DK, Vargas JR, Wilcox KS (2010) Increased coupling and altered glutamate transport currents in astrocytes following kainic-acid-induced status epilepticus. Neurobiol Dis 40:573–585

    PubMed  CAS  PubMed Central  Google Scholar 

  • Tanaka K, Watase K, Manabe T, Yamada K, Watanabe M, Takahashi K, Iwama H, Nishikawa T, Ichihara 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

    PubMed  CAS  Google Scholar 

  • Tang FR, Lee WL (2001) Expression of the group II and III metabotropic glutamate receptors in the hippocampus of patients with mesial temporal lobe epilepsy. J Neurocytol 30:137–143

    PubMed  CAS  Google Scholar 

  • Tessler S, Danbolt NC, Faull RLM, Storm-Mathisen J, Emson PC (1999) Expression of the glutamate transporters in human temporal lobe epilepsy. Neuroscience 88:1083–1091

    PubMed  CAS  Google Scholar 

  • Theis M, Giaume C (2012) Connexin-based intercellular communication and astrocyte heterogeneity. Brain Res 1487:88–98

    PubMed  CAS  Google Scholar 

  • Theofilas P, Brar S, Stewart KA, Shen HY, Sandau US, Poulsen D, Boison D (2011) Adenosine kinase as a target for therapeutic antisense strategies in epilepsy. Epilepsia 52:589–601

    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

    PubMed  CAS  PubMed Central  Google Scholar 

  • Torres A, Wang F, Xu Q, Fujita T, Dobrowolski R, Willecke K, Takano T, Nedergaard M (2012) Extracellular Ca(2)(+) acts as a mediator of communication from neurons to glia. Sci Signal 5:ra8

    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

    PubMed  CAS  Google Scholar 

  • Traynelis SF, Dingledine R (1989) Role of extracellular space in hyperosmotic suppression of potassium-induced electrographic seizures. J Neurophysiol 61:927–938

    PubMed  CAS  Google Scholar 

  • Ulas J, Satou T, Ivins KJ, Kesslak JP, Cotman CW, Balázs R (2000) Expression of metabotropic glutamate receptor 5 is increased astrocytes after kainate-induced epileptic seizures. Glia 30:352–361

    PubMed  CAS  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

    PubMed  CAS  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

    PubMed  CAS  PubMed Central  Google Scholar 

  • Vezzani A, Ravizza T, Balosso S, Aronica E (2008) Glia as a source of cytokines: implications for neuronal excitability and survival. Epilepsia 49(Suppl 2):24–32

    PubMed  CAS  Google Scholar 

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

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  • Vezzani A, Friedman A, Dingledine RJ (2012) The role of inflammation in epileptogenesis. Neuropharmacology 69:16–24

    PubMed  PubMed Central  Google Scholar 

  • Vianna EP, Ferreira AT, Dona F, Cavalheiro EA, da Silva Fernandes MJ (2005) Modulation of seizures and synaptic plasticity by adenosinergic receptors in an experimental model of temporal lobe epilepsy induced by pilocarpine in rats. Epilepsia 46(Suppl 5):166–173

    PubMed  CAS  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

    PubMed  CAS  Google Scholar 

  • Wallraff A, Kohling 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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  PubMed Central  Google Scholar 

  • Watanabe T, Morimoto K, Hirao T, Suwaki H, Watase K, Tanaka K (1999) Amygdala-kindled and pentylenetetrazole-induced seizures in glutamate transporter GLAST-deficient mice. Brain Res 845:92–96

    PubMed  CAS  Google Scholar 

  • Williams DM, Lopes CM, Rosenhouse-Dantsker A, Connelly HL, Matavel A, Uchi J, McBeath E, Gray DA (2010) Molecular basis of decreased Kir4.1 function in SeSAME/EAST syndrome. J Am Soc Nephrol 21:2117–2129

    PubMed  CAS  PubMed Central  Google Scholar 

  • Wong M, Ess KC, Uhlmann EJ, Jansen LA, Li W, Crino PB, Mennerick S, Yamada KA, Gutmann DH (2003) Impaired glial glutamate transport in a mouse tuberous sclerosis epilepsy model. Ann Neurol 54:251–256

    PubMed  CAS  Google Scholar 

  • Xu L, Zeng LH, Wong M (2009) Impaired astrocytic gap junction coupling and potassium buffering in a mouse model of tuberous sclerosis complex. Neurobiol Dis 34:291–299

    PubMed  PubMed Central  Google Scholar 

  • Yao X, Hrabetova S, Nicholson C, Manley GT (2008) Aquaporin-4-deficient mice have increased extracellular space without tortuosity change. J Neurosci 28:5460–5464

    PubMed  CAS  PubMed Central  Google Scholar 

  • Ye ZC, Sontheimer H (1996) Cytokine modulation of glial glutamate uptake: a possible involvement of nitric oxide. Neuroreport 7:2181–2185

    PubMed  CAS  Google Scholar 

  • Yoon JJ, Green CR, O’Carroll SJ, Nicholson LF (2010) Dose-dependent protective effect of connexin43 mimetic peptide against neurodegeneration in an ex vivo model of epileptiform lesion. Epilepsy Res 92:153–162

    PubMed  CAS  Google Scholar 

  • Zhang H, Verkman AS (2008) Aquaporin-4 independent Kir4.1 K+ channel function in brain glial cells. Mol Cell Neurosci 37:1–10

    PubMed  PubMed Central  Google Scholar 

  • Zimmermann H, Braun N (1996) Extracellular metabolism of nucleotides in the nervous system. J Auton Pharmacol 16:397–400

    PubMed  CAS  Google Scholar 

  • Zurolo E, de Groot M, Iyer A, Anink J, Van Vliet EA, Heimans JJ, Reijneveld JC, Gorter JA, Aronica E (2012) Regulation of Kir4.1 expression in astrocytes and astrocytic tumors: a role for interleukin-1 beta. J Neuroinflamm 9:280

    CAS  Google Scholar 

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Acknowledgements

Supported by DFG (SFB/TR3, TP C1; SPP1172, SE774/3–2) and EU (FP7–202167 NeuroGLIA; ESF EuroEPINOMICS).

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Correspondence to Christian Steinhäuser .

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Bedner, P., Steinhäuser, C. (2014). Crucial Role for Astrocytes in Epilepsy. In: Parpura, V., Verkhratsky, A. (eds) Pathological Potential of Neuroglia. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-0974-2_8

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