ECS Dynamism and Its Influence on Neuronal Excitability and Seizures

  • Robert Colbourn
  • Aditi Naik
  • Sabina HrabetovaEmail author


Seizure activity is governed by changes in normal neuronal physiology that lead to a state of neuronal hyperexcitability and synchrony. There is a growing body of research and evidence suggesting that alterations in the volume fraction (α) of the brain’s extracellular space (ECS) have the ability to prolong or even initiate seizures. These ictogenic effects likely occur due to the ECS volume being critically important in determining both the concentration of neuroactive substances contained within it, such as ions and neurotransmitters, and the effect of electric field-mediated interactions between neurons. Changes in the size of the ECS likely both precede a seizure, assisting in its initiation, and occur during a seizure, assisting in its maintenance. Different cellular ion and water transporters and channels are essential mediators in determining neuronal excitability and synchrony and can do so through alterations in ECS volume and/or through non-ECS volume related mechanisms. This review will parse out the relationships between how the ECS volume changes during normal physiology and seizures, how those changes might alter neuronal physiology to promote seizures, and what ion and water transporters and channels are important in linking ECS volume changes and seizures.


Extracellular space Diffusion Seizure Volume fraction Glia 



Funding was provided by the New York State Office of People with Developmental Disabilities (OPWDD) in the form of a fellowship for Robert Colbourn.


  1. 1.
    Behr C, Goltzene MA, Kosmalski G, Hirsch E, Ryvlin P (2016) Epidemiology of epilepsy. Rev Neurol (Paris) 172(1):27–36. CrossRefGoogle Scholar
  2. 2.
    Brodie MJ, Barry SJ, Bamagous GA, Norrie JD, Kwan P (2012) Patterns of treatment response in newly diagnosed epilepsy. Neurology 78(20):1548–1554. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Bromfield EB, Cavazos JE, Sirven JI (2006) An introduction to epilepsy. American Epilepsy Society, West HartfordGoogle Scholar
  4. 4.
    Staley K (2015) Molecular mechanisms of epilepsy. Nat Neurosci 18(3):367–372. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Pitkanen A, Lukasiuk K, Dudek FE, Staley KJ (2015) Epileptogenesis. Cold Spring Harb Perspect Med. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Goldenberg MM (2010) Overview of drugs used for epilepsy and seizures: etiology, diagnosis, and treatment. P T 35(7):392–415PubMedPubMedCentralGoogle Scholar
  7. 7.
    Korogod N, Petersen CC, Knott GW (2015) Ultrastructural analysis of adult mouse neocortex comparing aldehyde perfusion with cryo fixation. Elife. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Syková E (2004) Extrasynaptic volume transmission and diffusion parameters of the extracellular space. Neuroscience 129(4):861–876. CrossRefPubMedGoogle Scholar
  9. 9.
    Kamali-Zare P, Nicholson C (2013) Brain extracellular space: geometry, matrix and physiological importance. Basic Clin Neurosci 4(4):282–286PubMedPubMedCentralGoogle Scholar
  10. 10.
    Syková E, Nicholson C (2008) Diffusion in brain extracellular space. Physiol Rev 88(4):1277–1340. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Wolak DJ, Thorne RG (2013) Diffusion of macromolecules in the brain: implications for drug delivery. Mol Pharm 10(5):1492–1504. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Nicholson C, Phillips JM, Gardner-Medwin AR (1979) Diffusion from an iontophoretic point source in the brain: role of tortuosity and volume fraction. Brain Res 169(3):580–584CrossRefPubMedGoogle Scholar
  13. 13.
    Dityatev A, Seidenbecher CI, Schachner M (2010) Compartmentalization from the outside: the extracellular matrix and functional microdomains in the brain. Trends Neurosci 33(11):503–512. CrossRefPubMedGoogle Scholar
  14. 14.
    Almond A (2005) Towards understanding the interaction between oligosaccharides and water molecules. Carbohydr Res 340(5):907–920. CrossRefPubMedGoogle Scholar
  15. 15.
    Galtrey CM, Fawcett JW (2007) The role of chondroitin sulfate proteoglycans in regeneration and plasticity in the central nervous system. Brain Res Rev 54(1):1–18. CrossRefPubMedGoogle Scholar
  16. 16.
    Hrabetova S, Masri D, Tao L, Xiao F, Nicholson C (2009) Calcium diffusion enhanced after cleavage of negatively charged components of brain extracellular matrix by chondroitinase ABC. J Physiol 587(Pt 16):4029–4049. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Yamaguchi Y (2000) Lecticans: organizers of the brain extracellular matrix. Cell Mol Life Sci 57(2):276–289. CrossRefPubMedGoogle Scholar
  18. 18.
    Oohashi T, Edamatsu M, Bekku Y, Carulli D (2015) The hyaluronan and proteoglycan link proteins: organizers of the brain extracellular matrix and key molecules for neuronal function and plasticity. Exp Neurol 274(Pt B):134–144. CrossRefPubMedGoogle Scholar
  19. 19.
    Zimmermann DR, Dours-Zimmermann MT (2008) Extracellular matrix of the central nervous system: from neglect to challenge. Histochem Cell Biol 130(4):635–653. CrossRefPubMedGoogle Scholar
  20. 20.
    Ruoslahti E (1996) Brain extracellular matrix. Glycobiology 6(5):489–492CrossRefPubMedGoogle Scholar
  21. 21.
    Novak U, Kaye AH (2000) Extracellular matrix and the brain: components and function. J Clin Neurosci 7(4):280–290. CrossRefPubMedGoogle Scholar
  22. 22.
    Thorne RF, Legg JW, Isacke CM (2004) The role of the CD44 transmembrane and cytoplasmic domains in co-ordinating adhesive and signalling events. J Cell Sci 117(Pt 3):373–380. CrossRefPubMedGoogle Scholar
  23. 23.
    Carulli D, Rhodes KE, Brown DJ, Bonnert TP, Pollack SJ, Oliver K, Strata P, Fawcett JW (2006) Composition of perineuronal nets in the adult rat cerebellum and the cellular origin of their components. J Comp Neurol 494(4):559–577. CrossRefPubMedGoogle Scholar
  24. 24.
    Wyckoff RW, Young JZ (1956) The motorneuron surface. Proc R Soc Lond B Biol Sci 144(917):440–450CrossRefPubMedGoogle Scholar
  25. 25.
    Van Harreveld A, Crowell J, Malhotra SK (1965) A study of extracellular space in central nervous tissue by freeze-substitution. J Cell Biol 25:117–137CrossRefPubMedCentralGoogle Scholar
  26. 26.
    Rall DP, Oppelt WW, Patlack CS (1962) Extracellular space of brain as determined by diffusion of inulin from the ventricular system. Life Sci 1(2):43–48CrossRefGoogle Scholar
  27. 27.
    Tønnesen J, Inavalli V, Nägerl UV (2018) Super-resolution imaging of the extracellular space in living brain tissue. Cell 172(5):1108–1121 e1115. CrossRefPubMedGoogle Scholar
  28. 28.
    Hrabetova S, Nicholson C (2007) Biophysical properties of brain extracellular space explored with ion-selective microelectrodes, integrative optical imaging and related techniques. In: Michael AC, Borland LM (eds) Electrochemical methods for neuroscience. Frontiers in Neuroengineering, Boca RatonGoogle Scholar
  29. 29.
    Nicholson C (1993) Ion-selective microelectrodes and diffusion measurements as tools to explore the brain cell microenvironment. J Neurosci Methods 48(3):199–213CrossRefPubMedGoogle Scholar
  30. 30.
    Syková E, Hník P, Vyklický L (1981) Ion-selective microelectrodes and their use in excitable tissues. Plenum, New YorkCrossRefGoogle Scholar
  31. 31.
    Kaur G, Hrabetova S, Guilfoyle DN, Nicholson C, Hrabe J (2008) Characterizing molecular probes for diffusion measurements in the brain. J Neurosci Methods 171(2):218–225. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Nicholson C, Phillips JM (1981) Ion diffusion modified by tortuosity and volume fraction in the extracellular microenvironment of the rat cerebellum. J Physiol 321:225–257CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Nicholson C, Hrabetova S (2017) Brain extracellular space: the final frontier of neuroscience. Biophys J 113(10):2133–2142. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Odackal J, Colbourn R, Odackal NJ, Tao L, Nicholson C, Hrabetova S (2017) Real-time iontophoresis with tetramethylammonium to quantify volume fraction and tortuosity of brain extracellular space. J Vis Exp. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Voipio JPM, MacLeod K (1994) Ion-sensitive microelectrodes. In: Ogden D (ed) Microelectrode techniques—the plymouth workshop handbook, 2nd edn. The Company of Biologists Limited, Cambridge, pp 275–316Google Scholar
  36. 36.
    Dietzel I, Heinemann U, Hofmeier G, Lux HD (1980) Transient changes in the size of the extracellular space in the sensorimotor cortex of cats in relation to stimulus-induced changes in potassium concentration. Exp Brain Res 40(4):432–439CrossRefPubMedGoogle Scholar
  37. 37.
    Hrabetova S, Cognet L, Rusakov DA, Nagerl UV (2018) Unveiling the extracellular space of the brain: from super-resolved microstructure to in vivo function. J Neurosci 38(44):9355–9363. CrossRefPubMedGoogle Scholar
  38. 38.
    Kume-Kick J, Mazel T, Voříšek I, Hrabetova S, Tao L, Nicholson C (2002) Independence of extracellular tortuosity and volume fraction during osmotic challenge in rat neocortex. J Physiol 542(Pt 2):515–527CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Lehmenkühler A, Syková E, Svoboda J, Zilles K, Nicholson C (1993) Extracellular space parameters in the rat neocortex and subcortical white matter during postnatal development determined by diffusion analysis. Neuroscience 55(2):339–351CrossRefPubMedGoogle Scholar
  40. 40.
    Syková E, Voříšek I, Antonova T, Mazel T, Meyer-Luehmann M, Jucker M, Hájek M, Ort M, Bureš J (2005) Changes in extracellular space size and geometry in APP23 transgenic mice: a model of Alzheimer’s disease. Proc Natl Acad Sci USA 102(2):479–484. CrossRefPubMedGoogle Scholar
  41. 41.
    Syková E, Mazel T, Hasenohrl RU, Harvey AR, Šimonová Z, Mulders WH, Huston JP (2002) Learning deficits in aged rats related to decrease in extracellular volume and loss of diffusion anisotropy in hippocampus. Hippocampus 12(2):269–279. CrossRefPubMedGoogle Scholar
  42. 42.
    Svoboda J, Syková E (1991) Extracellular space volume changes in the rat spinal cord produced by nerve stimulation and peripheral injury. Brain Res 560(1–2):216–224CrossRefPubMedGoogle Scholar
  43. 43.
    Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O’Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M (2013) Sleep drives metabolite clearance from the adult brain. Science 342(6156):373–377. CrossRefPubMedGoogle Scholar
  44. 44.
    Ding F, O’Donnell J, Xu Q, Kang N, Goldman N, Nedergaard M (2016) Changes in the composition of brain interstitial ions control the sleep-wake cycle. Science 352(6285):550–555. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Sherpa AD, Xiao F, Joseph N, Aoki C, Hrabetova S (2016) Activation of β-adrenergic receptors in rat visual cortex expands astrocytic processes and reduces extracellular space volume. Synapse 70(8):307–316. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Hodgkin AL, Huxley AF, Katz B (1952) Measurement of current-voltage relations in the membrane of the giant axon of Loligo. J Physiol 116(4):424–448CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Lux HD, Heinemann U, Dietzel I (1986) Ionic changes and alterations in the size of the extracellular space during epileptic activity. Adv Neurol 44:619–639PubMedGoogle Scholar
  48. 48.
    Murphy TR, Binder DK, Fiacco TA (2017) Turning down the volume: astrocyte volume change in the generation and termination of epileptic seizures. Neurobiol Dis 104:24–32. CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Dudek FE, Snow RW, Taylor CP (1986) Role of electrical interactions in synchronization of epileptiform bursts. Adv Neurol 44:593–617PubMedGoogle Scholar
  50. 50.
    Vargová L, Syková E (2014) Astrocytes and extracellular matrix in extrasynaptic volume transmission. Philos Trans R Soc Lond B Biol Sci 369(1654):20130608. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Vargová L, Syková E (2008) Extracellular space diffusion and extrasynaptic transmission. Physiol Res 57(Suppl 3):S89–S99PubMedGoogle Scholar
  52. 52.
    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(18):6164–6176. CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Syková E (1997) The extracellular space in the CNS: Its regulation, volume and geometry in normal and pathological neuronal function. Neuroscientist 3(1):28–41. CrossRefGoogle Scholar
  54. 54.
    Weiss SA, Faber DS (2010) Field effects in the CNS play functional roles. Front Neural Circuits 4:15. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Ransom BR, Yamate CL, Connors BW (1985) Activity-dependent shrinkage of extracellular space in rat optic nerve: a developmental study. J Neurosci 5(2):532–535CrossRefPubMedGoogle Scholar
  56. 56.
    Connors BW, Ransom BR, Kunis DM, Gutnick MJ (1982) Activity-dependent K + accumulation in the developing rat optic nerve. Science 216(4552):1341–1343CrossRefPubMedGoogle Scholar
  57. 57.
    Haj-Yasein NN, Jensen V, Ostby I, Omholt SW, Voipio J, Kaila K, Ottersen OP, Hvalby O, Nagelhus EA (2012) Aquaporin-4 regulates extracellular space volume dynamics during high-frequency synaptic stimulation: a gene deletion study in mouse hippocampus. Glia 60(6):867–874. CrossRefPubMedGoogle Scholar
  58. 58.
    Larsen BR, MacAulay N (2017) Activity-dependent astrocyte swelling is mediated by pH-regulating mechanisms. Glia 65(10):1668–1681. CrossRefPubMedGoogle Scholar
  59. 59.
    Larsen BR, Assentoft M, Cotrina ML, Hua SZ, Nedergaard M, Kaila K, Voipio J, MacAulay N (2014) Contributions of the Na+/K+-ATPase, NKCC1, and Kir4.1 to hippocampal K+ clearance and volume responses. Glia 62(4):608–622. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Ammann D (1986) Ion-selective microelectrodes. principles, design, and application. Springer-Verlag, BerlinCrossRefGoogle Scholar
  61. 61.
    Raimondo JV, Burman RJ, Katz AA, Akerman CJ (2015) Ion dynamics during seizures. Front Cell Neurosci 9:419. CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Šlais K, Voříšek I, Zoremba N, Homola A, Dmytrenko L, Syková E (2008) Brain metabolism and diffusion in the rat cerebral cortex during pilocarpine-induced status epilepticus. Exp Neurol 209(1):145–154. CrossRefPubMedGoogle Scholar
  63. 63.
    Traynelis SF, Dingledine R (1989) Role of extracellular space in hyperosmotic suppression of potassium-induced electrographic seizures. J Neurophysiol 61(5):927–938. CrossRefPubMedGoogle Scholar
  64. 64.
    de Curtis M, Uva L, Gnatkovsky V, Librizzi L (2018) Potassium dynamics and seizures: why is potassium ictogenic? Epilepsy Res 143:50–59. CrossRefPubMedGoogle Scholar
  65. 65.
    Gardner-Medwin AR (1983) Analysis of potassium dynamics in mammalian brain tissue. J Physiol 335:393–426CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    During MJ, Spencer DD (1993) Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet 341(8861):1607–1610CrossRefPubMedGoogle Scholar
  67. 67.
    Pena F, Tapia R (2000) Seizures and neurodegeneration induced by 4-aminopyridine in rat hippocampus in vivo: role of glutamate- and GABA-mediated neurotransmission and of ion channels. Neuroscience 101(3):547–561CrossRefPubMedGoogle Scholar
  68. 68.
    Kaila K, Ruusuvuori E, Seja P, Voipio J, Puskarjov M (2014) GABA actions and ionic plasticity in epilepsy. Curr Opin Neurobiol 26:34–41. CrossRefPubMedGoogle Scholar
  69. 69.
    Zhang M, Ladas TP, Qiu C, Shivacharan RS, Gonzalez-Reyes LE, Durand DM (2014) Propagation of epileptiform activity can be independent of synaptic transmission, gap junctions, or diffusion and is consistent with electrical field transmission. J Neurosci 34(4):1409–1419. CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Chang BS, Lowenstein DH (2003) Epilepsy. N Engl J Med 349(13):1257–1266. CrossRefPubMedGoogle Scholar
  71. 71.
    McBain CJ, Traynelis SF, Dingledine R (1990) Regional variation of extracellular space in the hippocampus. Science 249(4969):674–677CrossRefPubMedGoogle Scholar
  72. 72.
    Murphy TR, Davila D, Cuvelier N, Young LR, Lauderdale K, Binder DK, Fiacco TA (2017) Hippocampal and cortical pyramidal neurons swell in parallel with astrocytes during acute hypoosmolar stress. Front Cell Neurosci 11:275. CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Andrew RD, Fagan M, Ballyk BA, Rosen AS (1989) Seizure susceptibility and the osmotic state. Brain Res 498(1):175–180CrossRefPubMedGoogle Scholar
  74. 74.
    Ballyk BA, Quackenbush SJ, Andrew RD (1991) Osmotic effects on the CA1 neuronal population in hippocampal slices with special reference to glucose. J Neurophysiol 65(5):1055–1066. CrossRefPubMedGoogle Scholar
  75. 75.
    Kilb W, Dierkes PW, Syková E, Vargová L, Luhmann HJ (2006) Hypoosmolar conditions reduce extracellular volume fraction and enhance epileptiform activity in the CA3 region of the immature rat hippocampus. J Neurosci Res 84(1):119–129. CrossRefPubMedGoogle Scholar
  76. 76.
    Lauderdale K, Murphy T, Tung T, Davila D, Binder DK, Fiacco TA (2015) Osmotic edema rapidly increases neuronal excitability through activation of NMDA receptor-dependent slow inward currents in juvenile and adult hippocampus. ASN Neuro. CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Weigel PH (2015) Hyaluronan synthase: the mechanism of initiation at the reducing end and a pendulum model for polysaccharide translocation to the cell exterior. Int J Cell Biol 2015:367579. CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Saghyan A, Lewis DP, Hrabe J, Hrabetova S (2012) Extracellular diffusion in laminar brain structures exemplified by hippocampus. J Neurosci Methods 205(1):110–118. CrossRefPubMedGoogle Scholar
  79. 79.
    Toole BP (2001) Hyaluronan in morphogenesis. Semin Cell Dev Biol 12(2):79–87. CrossRefPubMedGoogle Scholar
  80. 80.
    Pivovarov AS, Calahorro F, Walker RJ (2018) Na+/K+-pump and neurotransmitter membrane receptors. Invert Neurosci 19(1):1. CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Thomas RC (1972) Electrogenic sodium pump in nerve and muscle cells. Physiol Rev 52(3):563–594. CrossRefPubMedGoogle Scholar
  82. 82.
    Holm TH, Lykke-Hartmann K (2016) Insights into the pathology of the α3 Na+/K+-ATPase ion pump in neurological disorders; lessons from animal models. Front Physiol 7:209. CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Vaillend C, Mason SE, Cuttle MF, Alger BE (2002) Mechanisms of neuronal hyperexcitability caused by partial inhibition of Na+-K+-ATPases in the rat CA1 hippocampal region. J Neurophysiol 88(6):2963–2978. CrossRefPubMedGoogle Scholar
  84. 84.
    Grisar T, Franck G, Schoffeniels E (1980) Glial control of neuronal excitability in mammals: II. Enzymatic evidence: two molecular forms of the (Na+,K+)-ATPase in brain. Neurochem Int 2C:311–320CrossRefPubMedGoogle Scholar
  85. 85.
    Larsen BR, Stoica A, MacAulay N (2016) Managing brain extracellular K+ during neuronal activity: the physiological role of the Na+/K+-ATPase subunit isoforms. Front Physiol 7:141. CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Stoica A, Larsen BR, Assentoft M, Holm R, Holt LM, Vilhardt F, Vilsen B, Lykke-Hartmann K, Olsen ML, MacAulay N (2017) The α2β2 isoform combination dominates the astrocytic Na+/K+-ATPase activity and is rendered nonfunctional by the α2.G301R familial hemiplegic migraine type 2-associated mutation. Glia 65(11):1777–1793. CrossRefPubMedGoogle Scholar
  87. 87.
    Larsen BR, Stoica A, MacAulay N (2019) Developmental maturation of activity-induced K+ and pH transients and the associated extracellular space dynamics in the rat hippocampus. J Physiol 597(2):583–597. CrossRefPubMedGoogle Scholar
  88. 88.
    Attwell D, Laughlin SB (2001) An energy budget for signaling in the grey matter of the brain. J Cereb Blood Flow Metab 21(10):1133–1145. CrossRefPubMedGoogle Scholar
  89. 89.
    Lees GJ, Lehmann A, Sandberg M, Hamberger A (1990) The neurotoxicity of ouabain, a sodium-potassium ATPase inhibitor, in the rat hippocampus. Neurosci Lett 120(2):159–162CrossRefPubMedGoogle Scholar
  90. 90.
    Macaulay N, Zeuthen T (2012) Glial K+ clearance and cell swelling: key roles for cotransporters and pumps. Neurochem Res 37(11):2299–2309. CrossRefPubMedGoogle Scholar
  91. 91.
    de Los Heros P, Alessi DR, Gourlay R, Campbell DG, Deak M, Macartney TJ, Kahle KT, Zhang J (2014) The WNK-regulated SPAK/OSR1 kinases directly phosphorylate and inhibit the K+-Cl co-transporters. Biochem J 458(3):559–573. CrossRefPubMedGoogle Scholar
  92. 92.
    Kelley MR, Deeb TZ, Brandon NJ, Dunlop J, Davies PA, Moss SJ (2016) Compromising KCC2 transporter activity enhances the development of continuous seizure activity. Neuropharmacology 108:103–110. CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Dzhala V, Staley KJ (2015) Acute and chronic efficacy of bumetanide in an in vitro model of posttraumatic epileptogenesis. CNS Neurosci Ther 21(2):173–180. CrossRefPubMedGoogle Scholar
  94. 94.
    Edwards DA, Shah HP, Cao W, Gravenstein N, Seubert CN, Martynyuk AE (2010) Bumetanide alleviates epileptogenic and neurotoxic effects of sevoflurane in neonatal rat brain. Anesthesiology 112(3):567–575. CrossRefPubMedGoogle Scholar
  95. 95.
    Mazarati A, Shin D, Sankar R (2009) Bumetanide inhibits rapid kindling in neonatal rats. Epilepsia 50(9):2117–2122. CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Mares P (2009) Age- and dose-specific anticonvulsant action of bumetanide in immature rats. Physiol Res 58(6):927–930PubMedGoogle Scholar
  97. 97.
    Margineanu DG, Klitgaard H (2006) Differential effects of cation-chloride co-transport-blocking diuretics in a rat hippocampal slice model of epilepsy. Epilepsy Res 69(2):93–99. CrossRefPubMedGoogle Scholar
  98. 98.
    Moore YE, Kelley MR, Brandon NJ, Deeb TZ, Moss SJ (2017) Seizing control of KCC2: a new therapeutic target for epilepsy. Trends Neurosci 40(9):555–571. CrossRefPubMedGoogle Scholar
  99. 99.
    Hochman DW (2012) The extracellular space and epileptic activity in the adult brain: explaining the antiepileptic effects of furosemide and bumetanide. Epilepsia 53(Suppl 1):18–25. CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Holthoff K, Witte OW (1996) Intrinsic optical signals in rat neocortical slices measured with near-infrared dark-field microscopy reveal changes in extracellular space. J Neurosci 16(8):2740–2749CrossRefPubMedGoogle Scholar
  101. 101.
    Hamann S, Herrera-Perez JJ, Bundgaard M, Alvarez-Leefmans FJ, Zeuthen T (2005) Water permeability of Na+-K+-2Cl cotransporters in mammalian epithelial cells. J Physiol 568(Pt 1):123–135. CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O’Keeffe S, Phatnani HP, Guarnieri P, Caneda C, Ruderisch N, Deng S, Liddelow SA, Zhang C, Daneman R, Maniatis T, Barres BA, Wu JQ (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34(36):11929–11947. CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Uwera J, Nedergaard S, Andreasen M (2015) A novel mechanism for the anticonvulsant effect of furosemide in rat hippocampus in vitro. Brain Res 1625:1–8. CrossRefPubMedGoogle Scholar
  104. 104.
    MacAulay N, Zeuthen T (2010) Water transport between CNS compartments: contributions of aquaporins and cotransporters. Neuroscience 168(4):941–956. CrossRefPubMedGoogle Scholar
  105. 105.
    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(4):905–913. CrossRefPubMedGoogle Scholar
  106. 106.
    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(6):631–636. CrossRefPubMedGoogle Scholar
  107. 107.
    Zhang H, Verkman AS (2008) Aquaporin-4 independent Kir4.1 K+ channel function in brain glial cells. Mol Cell Neurosci 37(1):1–10. CrossRefPubMedGoogle Scholar
  108. 108.
    Ruiz-Ederra J, Zhang H, Verkman AS (2007) Evidence against functional interaction between aquaporin-4 water channels and Kir4.1 potassium channels in retinal Muller cells. J Biol Chem 282(30):21866–21872. CrossRefPubMedGoogle Scholar
  109. 109.
    Das A, 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 TLE is associated with astrocyte activation, inflammation, and altered expression of channels and receptors. Neuroscience 220:237–246. CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    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(9):814–825. CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    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(1):55–64. CrossRefPubMedGoogle Scholar
  112. 112.
    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 USA 107(32):14490–14495. CrossRefPubMedGoogle Scholar
  113. 113.
    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 USA 102(4):1193–1198. CrossRefPubMedGoogle Scholar
  114. 114.
    Coulter DA, Steinhauser C (2015) Role of astrocytes in epilepsy. Cold Spring Harb Perspect Med 5(3):a022434. CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Yao X, Hrabetova S, Nicholson C, Manley GT (2008) Aquaporin-4-deficient mice have increased extracellular space without tortuosity change. J Neurosci 28(21):5460–5464. CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Larsen BR, MacAulay N (2014) Kir4.1-mediated spatial buffering of K+: experimental challenges in determination of its temporal and quantitative contribution to K+ clearance in the brain. Channels (Austin) 8(6):544–550. CrossRefGoogle Scholar
  117. 117.
    Bevensee MO, Weed RA, Boron WF (1997) Intracellular pH regulation in cultured astrocytes from rat hippocampus. I. Role Of HCO3. J Gen Physiol 110(4):453–465CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Theparambil SM, Naoshin Z, Thyssen A, Deitmer JW (2015) Reversed electrogenic sodium bicarbonate cotransporter 1 is the major acid loader during recovery from cytosolic alkalosis in mouse cortical astrocytes. J Physiol 593(16):3533–3547. CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Sinning A, Hubner CA (2013) Minireview: pH and synaptic transmission. FEBS Lett 587(13):1923–1928. CrossRefPubMedGoogle Scholar
  120. 120.
    Yang T, Lin Z, Xie L, Wang Y, Pan S (2017) 4,4′-Diisothiocyanatostilbene-2,2′-disulfonic acid attenuates spontaneous recurrent seizures and vasogenic edema following lithium-pilocarpine induced status epilepticus. Neurosci Lett 653:51–57. CrossRefPubMedGoogle Scholar
  121. 121.
    Theparambil SM, Ruminot I, Schneider HP, Shull GE, Deitmer JW (2014) The electrogenic sodium bicarbonate cotransporter NBCe1 is a high-affinity bicarbonate carrier in cortical astrocytes. J Neurosci 34(4):1148–1157. CrossRefPubMedGoogle Scholar
  122. 122.
    Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65(1):1–105CrossRefPubMedGoogle Scholar
  123. 123.
    Haugeto O, Ullensvang K, Levy LM, Chaudhry FA, Honore T, Nielsen M, Lehre KP, Danbolt NC (1996) Brain glutamate transporter proteins form homomultimers. J Biol Chem 271(44):27715–27722CrossRefPubMedGoogle Scholar
  124. 124.
    Heller JP, Rusakov DA (2015) Morphological plasticity of astroglia: understanding synaptic microenvironment. Glia 63(12):2133–2151. CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Bradford HF (1995) Glutamate, GABA and epilepsy. Prog Neurobiol 47(6):477–511CrossRefPubMedGoogle Scholar
  126. 126.
    Piet R, Bonhomme R, Theodosis DT, Poulain DA, Oliet SH (2003) Modulation of GABAergic transmission by endogenous glutamate in the rat supraoptic nucleus. Eur J Neurosci 17(9):1777–1785CrossRefPubMedGoogle Scholar
  127. 127.
    Celio MR, Spreafico R, De Biasi S, Vitellaro-Zuccarello L (1998) Perineuronal nets: past and present. Trends Neurosci 21(12):510–515CrossRefPubMedGoogle Scholar
  128. 128.
    Oliet SH, Piet R, Poulain DA (2001) Control of glutamate clearance and synaptic efficacy by glial coverage of neurons. Science 292(5518):923–926. CrossRefPubMedGoogle Scholar
  129. 129.
    Whetsell WO Jr (1996) Current concepts of excitotoxicity. J Neuropathol Exp Neurol 55(1):1–13CrossRefPubMedGoogle Scholar
  130. 130.
    Abdullaev IF, Rudkouskaya A, Schools GP, Kimelberg HK, Mongin AA (2006) Pharmacological comparison of swelling-activated excitatory amino acid release and Cl currents in cultured rat astrocytes. J Physiol 572(Pt 3):677–689. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Robert Colbourn
    • 1
    • 2
  • Aditi Naik
    • 1
    • 2
  • Sabina Hrabetova
    • 1
    Email author
  1. 1.Department of Cell BiologySUNY Downstate Medical CenterBrooklynUSA
  2. 2.Neural and Behavioral Science Graduate ProgramSUNY Downstate Medical CenterBrooklynUSA

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