Advertisement

Abnormalities of GABA System and Human Pharmacoresistant Epilepsy

  • Sandra Orozco-Suárez
  • David Escalante-Santiago
  • Iris Angélica Feria-Romero
  • Monica E. Ureña-Guerrero
  • Luisa Rocha
  • Mario A. Alonso-Vanegas
  • Juana Villeda-Hernandez
  • Ana Luisa Velasco
Chapter

Abstract

Despite the availability of various newly developed antiepileptic drugs (AEDs), pharmacoresistance remains a major challenge in epilepsy management. Unraveling the mechanisms underlying AED resistance has been the focus of intense efforts, in order to develop new rationally designed therapies for as yet refractory epilepsies. Based on experimental and clinical studies, one of the major neurobiological theories that has been put forward is the target hypothesis, which suggests that AEDs are not effective because of target alterations in the epileptogenic brain. Several studies have shown that seizure activity results in altered expression of gamma-aminobutyric acid (GABA) components such as GABA transporters (GATs) and GABA receptors. Indeed, changes in the composition of subunits expression appear to affect the functioning of GABAergic neurotransmission. Here, we review the current literature on epilepsy-associated changes in the GABA system conducted in experimental models and observations made in patients with treatment-resistant epilepsy, as well as genetic abnormalities in the GABA system in refractory human epilepsy.

Keywords

Pharmacoresistant epilepsy GABA neurotransmission GABA ­receptors Human data Animal models GABA subunits Antiepileptic drugs 

Notes

Acknowledgments

This study was supported by the Research in Health Found, FIS/IMSS/PROT/548 grant and National Council for Sciences and Technology of Mexico (Grant 98386). We thank Dr. Erika Brust-Mascher for English improvement.

References

  1. Audenaert D, Schwartz E, Claeys KG, Claes L, Deprez L, Suls A. et al. Combined effect of bumetanide, bromide, and GABAergic agonists: an alternative treatment for intractable seizures. Epilepsy Behav. 2011;20:147–9.PubMedGoogle Scholar
  2. Arellano JI, Muñoz A, Ballesteros-Yañez I, Sola RG, DeFelipe J. Histopathology and reorganization of chandelier cells in the human epileptic sclerotic hippocampus. Brain. 2004;127:45–64.PubMedGoogle Scholar
  3. Audenaert D, Schwartz E, Claeys KG, et al. A novel GABRG2 mutation associated with febrile seizures. Neurology. 2006;67:687–90.PubMedGoogle Scholar
  4. Belhage B, Hansen GH, Schousboe A. Depolarization by K + and glutamate activates different neurotransmitter release mechanisms in GABAergic neurons: vesicular versus non-vesicular release of GABA. Neuroscience. 1993;54:1019–34.PubMedGoogle Scholar
  5. Ben-Ari Y, Giarsa JL, Tyzio R, Khazipov R. GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations. Physiol Rev. 2007;87:1215–84.PubMedGoogle Scholar
  6. Ben-Ari Y, Khalilov I, Kahle KT, Cherubini E. The GABA excitatory/inhibitory shift in brain maturation and neurological disorders. Neuroscientist. 2012;18(5):467–86.PubMedGoogle Scholar
  7. Benarroch E. GABAB receptors structure, functions, and clinical implications. Neurology. 2012;78:578–82.PubMedGoogle Scholar
  8. Blaesse P, Airaksinen MS, Rivera C, Kaila K. Cation-chloride cotransporters and neuronal function. Neuron. 2009;61:820–38.PubMedGoogle Scholar
  9. Bormann J. Electrophysiology of GABAA and GABAB receptor subtypes. Trends Neurosci. 1988;11:112–6.PubMedGoogle Scholar
  10. Bormann J, Feigenspan A. GABAC receptors. Trends Neurosci. 1995;18:515–9.PubMedGoogle Scholar
  11. Bowery NG. GABAB receptors and their significance in mammalian pharmacology. Trends Pharmacol Sci. 1989;10:401–7.PubMedGoogle Scholar
  12. Bragin DE, Sanderson JL, Peterson S, Connor JA, Müller WS. Development of epileptiform excitability in the deep entorhinal cortex after status epilepticus. Eur J Neurosci. 2009;30(4):611–24.PubMedGoogle Scholar
  13. Briggs SW, Galanopoulou AS. Altered GABA signaling in early life epilepsies. Neural Plast. 2011;2011:527605.PubMedGoogle Scholar
  14. Brooks-Kayal AR, Shumate MD, Jin H, Rikhter TY, Coulter DA. Selective changes in single cell GABA(A) receptor subunit expression and function in temporal lobe epilepsy. Nat Med. 1998;4:1166–72.PubMedGoogle Scholar
  15. Buró D, Kamatchi G. GABAA receptor subtypes: from pharmacology to molecular biology. FASEB J. 1991;5:2916–23.Google Scholar
  16. Cancedda L, Fiumelli H, Chen K, Poo MM. Excitatory GABA action is essential for morphological maturation of cortical neurons in vivo. J Neurosci. 2007;27:5224–35.PubMedGoogle Scholar
  17. Cohen I, Navarro V, Clemenceau S, Baulac M, Miles R. On the origin of interictal activity in human temporal lobe epilepsy in vitro. Science. 2002;298:1418–21.PubMedGoogle Scholar
  18. Cossett P, Liu L, Brisebois K,Dong H, Lortie A, Vannase M, et al. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet. 2002;31:184–9.PubMedGoogle Scholar
  19. Crino PB, Duhaime AC, Baltuch G, White R. Differential expression of glutamate and GABA-A receptor subunit mRNA in cortical dysplasia. Neurology. 2001;56:906–13.PubMedGoogle Scholar
  20. Dibbens LM, Feng HJ, Richards MC,Harkin LA,Hudqson BL, Scott D, et al. GABRD encoding a protein for extra- or peri-synaptic GABA-A receptors is a susceptibility locus for generalized epilepsies. Hum Mol Genet. 2004;13:1315–9.PubMedGoogle Scholar
  21. Ding L, Feng HJ, Macdonald RL, Botzolakis EJ, Hu N, Gallagher MJ. GABA(A) receptor alpha−1 subunit mutation A322D associated with autosomal dominant juvenile myoclonic epilepsy reduces the expression and alters the composition of wild type GABA(A) receptors. J Biol Chem. 2010;285:26390–405.PubMedGoogle Scholar
  22. Dzhala VI, Talos DM, Sdrulla DA, Brumback AC, Mathews GC, Benke TA, et al. NKCC1 transporter facilitates seizures in the developing brain. Nat Med. 2005;11:1205–13.PubMedGoogle Scholar
  23. Enz R, Cutting GR. Molecular composition of GABAC receptors. Vision Res. 1998;38:1431–41.PubMedGoogle Scholar
  24. Enz R, Cutting GR. GABAC receptor r subunits are heterogeneously expressed in the human CNS and form homo- and heterooligomers with distinct properties. Eur J Neurosci. 1999;11:41–50.PubMedGoogle Scholar
  25. Escalante-Santiago E, Feria-Romero I, Rocha L, Alonso M, Villeda J, Ureña-Guerrero ME, Munguia J, Nicolini-Sánchez H, Velasco AL, Chávez L, Orozco-Suárez S (in press) Changes in the expression of mRNA and protein of the GABA system in pharmacoresistant temporal lobe epilepsy Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, 2010Google Scholar
  26. Farrant M, Nusser Z. Variations on an inhibitory theme: phasic and tonic activation of GABAA receptors. Nat Rev Neurosci. 2005;6:215–29.PubMedGoogle Scholar
  27. Feigenspan A, Bormann J. GABA-gated Cl2 channels in the rat retina. Prog Retinal Eye Res. 1998;17:99–126.Google Scholar
  28. Feucht M, Fuchs K, Pichlbauer E, Hornik K, Scharfetter J, Goessler R, et al. Possible association between childhood absence epilepsy and the gene encoding GABRB3. Biol Psychiatry. 1999;46:997–1002.PubMedGoogle Scholar
  29. Fritschy JM, Kiener T, Bouilleret V, Loup F. GABAergic neurons and GABAA-receptors in temporal lobe epilepsy. Neurochem Int. 1999;34:435–45.PubMedGoogle Scholar
  30. Garrett KM, Duman RS, Saito N,Blume AJ, Vitek MP, Tallman JF, et al. Isolation of a cDNA clone for the alpha subunit of the human GABA-A receptor. Biochem Biophys Res Commun. 1988;156:1039–45.PubMedGoogle Scholar
  31. Gerelsaikhan T, Turner RJ. Transmembrane topology of the secretory Na+-K+-2Cl cotransporter NKCC1 studied by in vitro translation. J Biol Chem. 2000;275:40471–7.PubMedGoogle Scholar
  32. Gibbs III JW, Shumate M, Coulter D. Differential epilepsy-associated alterations in postsynaptic GABAA receptor function in dentate granule and CA1 neurons. J Neurophysiol. 1997;77: 1924–38.PubMedGoogle Scholar
  33. Glykys J, Mody I. Hippocampal network hyperactivity after selective reduction of tonic inhibition in GABA A receptor alpha5 subunit-deficient mice. J Neurophysiol. 2006;95:2796–807.PubMedGoogle Scholar
  34. Glykys J, Dzhala VI, Kuchibhotla KV, Feng G, Kuner T, Augustine G, et al. Differences in cortical versus subcortical GABAergic signaling a candidate mechanism of electroclinical uncoupling of neonatal seizures. Neuron. 2009;63:657–72.PubMedGoogle Scholar
  35. Gulyas AI, Sik A, Payne JA, Kaila K, Freund TF. The KCI cotransporter, KCC2, is highly expressed in the vicinity of excitatory synapses in the rat hippocampus. Eur J Neurosci. 2001;13:2205–17.PubMedGoogle Scholar
  36. Harkin LA, Bowser DN, Dibbens LM, Singh R., Phillips F, Wallace RH, et al. Truncation of the GABA-A-receptor gamma-2 subunit in a family with generalized epilepsy with febrile seizures plus. Am J Hum Genet. 2002;70:530–6.PubMedGoogle Scholar
  37. Hertz L, Schousboe A. Primary cultures of GABAergic and glutamatergic neurons as model systems to study neurotransmitter functions. Differentiated cells. In: Vernadakis A, Privat A, Lauder JM, Timiras PS, Giacobini E, editors. Model systems of development and aging of the nervous system. Boston: Martinus Nijhoff Publishing; 1987.Google Scholar
  38. Hilton GD, Ndubuizu A, Nunez JL, McCarthy MM. Simultaneous glutamate and GABA(A) receptor agonist administration increases calbindin levels and prevents hippocampal damage induced by either agent alone in a model of perinatal brain injury. Brain Res Dev Brain Res. 2005;159: 99–111.PubMedGoogle Scholar
  39. Houser CR, Esclapez M. Downregulation of the α5 subunit of the GABAA receptor in the ­pilocarpine model of temporal lobe epilepsy. Hippocampus. 2003;13:633–45.PubMedGoogle Scholar
  40. Iversen LL, Kelly JS. Uptake and metabolism of gamma-aminobutyric acid by neurones and glial cells. Biochem Pharmacol. 1975;24:933–8.PubMedGoogle Scholar
  41. Jacob TC, Moss SJ, Jurd R. GABA(A) receptor trafficking and its role in the dynamic modulation of neuronal inhibition. Nat Rev Neurosci. 2008;9:331–43.PubMedGoogle Scholar
  42. Jensen FE. Neonatal seizures: an update on mechanisms and management. Clin Perinatol. 2009;36:881–900.PubMedGoogle Scholar
  43. Johnston GA. GABAC receptors: relatively simple transmitter gated ion channels? Trends Pharmacol Sci. 1996;17:319–23.PubMedGoogle Scholar
  44. Joshi S, Rajasekaran, K Kapur J (2011) GABAergic transmission in temporal lobe epilepsy: The role of neurosteroids. Exp NeurolGoogle Scholar
  45. Kahle KT, Staley KJ. Cation-chloride cotransporters as pharmacological targets in the treatment of epilepsy. In: Alvarez-Leefmans F, Delpire E, editors. Physiology and pathology of chloride transporters and channels in the nervous system. New York: Academic; 2009.Google Scholar
  46. Kananura C, Haug K, Sander T, Runge u, Gu W, Hallmann K, et al. A splice-site mutation in GABRG2 associated with childhood absence epilepsy and febrile convulsions. Arch Neurol. 2002;59:1137–41.PubMedGoogle Scholar
  47. Kang JQ, Shen W, Macdonald RL. Why does fever trigger febrile seizures? GABAA receptor gamma2 subunit mutations associated with idiopathic generalized epilepsies have temperature-­dependent trafficking deficiencies. J Neurosci. 2006;6:2590–7.Google Scholar
  48. Kaupmann K, Malitschek B, Schuler V. GABA(B)-receptor subtypes assemble into functional heteromeric complexes. Nature. 1998;396:683–7.PubMedGoogle Scholar
  49. Kaupmann K, Cryan JF, Wellendorph P, Mombereau C, Sansig G, Klebs K, et al. Specific gamma-hydroxybutyrate-binding sites but loss of pharmacological effects of gamma-hydroxybutyrate in GABA(B)(1)- deficient mice. Eur J Neurosci. 2003;18:2722–30.PubMedGoogle Scholar
  50. Klitgaard H, Matagne A, Grimee R, Vanneste-Goemaere J, Margineanu DG. Electrophysiological, neurochemical and regional effects of levetiracetam in the rat pilocarpine model of temporal lobe epilepsy. Seizure. 2003;12:92–100.PubMedGoogle Scholar
  51. Korpi ER, Gründer G, Lüddens H. Drug interactions at GABAA receptors. Prog Neurobiol. 2002;67:113–59.PubMedGoogle Scholar
  52. Lambert JJ, Belelli D, Peden DR, Vardy AW, Peters JA. Neurosteroid modulation of GABAA receptors. Prog Neurobiol. 2003;71:67–80.PubMedGoogle Scholar
  53. Laschet JJ, Kurcewicz I, Minier F, Trottier S, Khallov-Laschet J, Louvel J.et al. Dysfunction of GABAA receptor glycolysis-dependent modulation in human partial epilepsy. Proc Natl Acad Sci U S A. 2007;104:3472–7.PubMedGoogle Scholar
  54. Lee TS, Bjørnsen LP, Paz C, Kim JH, Spencer SS, Spencer DD, et al. GAT1 and GAT3 expression are differently localized in the human epileptogenic hippocampus. Acta Neuropathol. 2006;111:351e363.Google Scholar
  55. Leidenheimer NJ. Regulation of excitation by GABA(A) receptor internalization. Results Probl Cell Differ. 2008;44:1–28.PubMedGoogle Scholar
  56. Lenzen KP, Heils A, Lorenz S,Hempelman A, Sander T. Association analysis of the arg220-to-his variation of the human gene encoding the GABA delta subunit with idiopathic generalized epilepsy. Epilepsy Res. 2005;65:53–7.PubMedGoogle Scholar
  57. Li RW, Yu W, Christie S, Miralles CP, Bai J, Loturco JJ, et al. Disruption of postsynaptic GABA receptor clusters leads to decreased GABAergic innervation of pyramidal neurons. J Neurochem. 2005;95:756–70.PubMedGoogle Scholar
  58. Löscher W, Potchka H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci. 2005;6(8):591–602.PubMedGoogle Scholar
  59. Löscher W, Schmidt D. New horizons in the development of antiepileptic drugs: the search for new targets. Epilepsy Res. 2001;60:77–159.Google Scholar
  60. Löscher W, Puskarjov, M, Kaila K (2012) Cation-chloride cotransporters NKCC1 and KCC2 as potential targets for novel antiepileptic and antiepileptogenic treatments. Neuropharmacology. 2012; http://dx.doi.org/10.1016/j.neuropharmacol.2012.05.045
  61. Lü JJ, Zhang YH, Pan H, Chen YC, Liu XY, Jiang YW, et al. Case-control study and transmission/disequilibrium tests of the genes encoding GABRA5 and GABRB3 in a Chinese population affected by childhood absence epilepsy. Chin Med J (Engl). 2004;117:1497–14501.Google Scholar
  62. Lund IV, Hu Y, Raol YH, Benham RS, Faris R, Russek SJ, et al. BDNF selectively regulates GABAA receptor transcription by activation of the JAK/STAT pathway. Sci Signal. 2008;1(41):ra9.PubMedGoogle Scholar
  63. Maa E, Bainbridge J, Spitz MC, Staley KJ. Oral bumetanide add-on therapy in refractory temporal lobe epilepsy. Epilepsia. 2007;48(Suppl. 6) [abstract # 3.222]Google Scholar
  64. Macdonald RL, Kang JQ, Gallagher MJ. Mutations in GABAA receptor subunits associated with genetic epilepsies. J Physiol. 2010;588:1861–9.PubMedGoogle Scholar
  65. Maljevic S, Krampfl K, Cobilanschi J, Filgen N, Beyer S. Weber YG, et al. A mutation in the GABA-A receptor alpha-1-subunit is associated with absence epilepsy. Ann Neurol. 2006;59:983–7.PubMedGoogle Scholar
  66. Manent JB, Jorquera I, Ben Ari Y, Aniksztejn L, Represa A. Glutamate acting on AMPA but not NMDA receptors modulates the migration of hippocampal interneurons. J Neurosci. 2006;26:5901–9.PubMedGoogle Scholar
  67. Marshall FH, Jones KA, Kaupmann K, Bettler B. GABAB receptors—the first 7TM heterodimers. Trends Pharmacol Sci. 1999;20:396–9.PubMedGoogle Scholar
  68. Mathern GW, Mendoza D, Lozada A, Pretorius JK, Danbolt NV, Nelson N, et al. Hippocampal GABA and glutamate transporter immunoreactivity in patients with temporal lobe epilepsy. Neurology. 1999;52:453e–72e.Google Scholar
  69. Mathern GW, Adelson PD, Cahan LD, Leite JP. Hippocampal neuron damage in human epilepsy. Meyer’s hypothesis revisited. Prog Brain Res. 2002;135:237–51.PubMedGoogle Scholar
  70. McGeer PL, McGeer EG. Amino acid neurotransmitters. In: Siegel GJ, Agranoff BW, Albers RW, Molinoff PB, editors. Basic neurochemistry: molecular, cellular and medical aspects. 4th ed. New York: Raven; 1989.Google Scholar
  71. Mercado A, Mount DB, Gamba G. Electroneutral cation-chloride cotransporters in the central nervous system. Neurochem Res. 2004;29:17–25.PubMedGoogle Scholar
  72. Mihalek RM, Banerjee PK, Korpi ER, et al. Attenuated sensitivity to neuroactive steroids in gamma-aminobutyrate type A receptor delta subunit knockout mice. Proc Natl Acad Sci U S A. 1999;96:12905–10.PubMedGoogle Scholar
  73. Mihalek RM, Bowers BJ, Wehner JM, Kralic JE, VanDoren MJ, Morrow AL. Homanics GE.GABA(A)-receptor delta subunit knockout mice have multiple defects in behavioral responses to ethanol. Alcohol Clin Exp Res. 2001;25:1708–18.PubMedGoogle Scholar
  74. Muñoz A, Mendez P, DeFelipe J, Alvarez-Leefmans FJ. Cation-chloride cotransporters and GABA-ergic innervation in the human epileptic hippocampus. Epilepsia. 2007;48:663–73.PubMedGoogle Scholar
  75. Nishimura T, Schwarzer C, Gasser E, Kato N, Vezzani A, Sperk G. Altered expression of GABA(A) and GABA(B) receptor subunit mRNAs in the hippocampus after kindling and electrically induced status epilepticus. Neuroscience. 2005;134:691–704.PubMedGoogle Scholar
  76. Ogris W, Poltl A, Hauer B, Ernst M, Oberto A, Wulff P, et al. Affinity of various benzodiazepine site ligands in mice with a point mutation in the GABAA receptor γ2 subunit. Biochem Pharmacol. 2004;68:1621–9.PubMedGoogle Scholar
  77. Olsen RW, Sieghart W. International Union of Pharmacology. LXX. Subtypes of gamma-­aminobutyric acid (A) receptors: classification on the basis of subunit composition, pharmacology, and function. Update. Pharmacol Rev. 2008;60:243–60.PubMedGoogle Scholar
  78. Pavlov I, Savtchenko LP, Kullmann DM, Semyanov A, Walker MC. Outwardly rectifying tonically active GABAA receptors in pyramidal cells modulate neuronal offset, not gain. J Neurosci. 2009;29:15341–50.PubMedGoogle Scholar
  79. Payne JA, Stevenson TJ, Donaldson LF. Molecular characterization of a putative K-Cl cotransporter in rat brain. A neuronal-specific isoform. J Biol Chem. 1996;271:16245–52.PubMedGoogle Scholar
  80. Peng Z, Huang CS, Stell BM, Mody I, Houser CR. Altered expression of the d subunit of the GABAA receptor in a mouse model of temporal lobe epilepsy. J Neurosci. 2004;24:8629–39.PubMedGoogle Scholar
  81. Pirker S, Schwarzer C, Czech T, Baungartner C, Pockberg H, Maier H et al. Increased expression of GABAA receptor β-subunits in the hippocampus of patients with temporal lobe epilepsy. J Neuropathol Exp Neurol. 2003;62:820–34.PubMedGoogle Scholar
  82. Remy S, Beck H. Molecular and cellular mechanisms of pharmacoresistance in epilepsy. Brain. 2006;129:18–35.PubMedGoogle Scholar
  83. Rivera C, Voipio J, Payne JA, Rusuvuori E, Lahtinen H, Lamsa K, et al. The K+/Cl co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature. 1999;397:251–5.PubMedGoogle Scholar
  84. Rivera C, Li H, Thomas-Crusells J, Lahtinen H,Viitanen T, Nanobashuili A, et al. BDNF-induced TrkB activation down-regulates the K+-Cl+ cotransporter KCC2 and impairs neuronal Cl extrusion. J Cell Biol. 2002;159:747–52.PubMedGoogle Scholar
  85. Rogawski MA, Löscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci. 2004;5:553–64.PubMedGoogle Scholar
  86. Schmidt D, Löscher W. Drug resistance in epilepsy: putative neurobiologic and clinical mechanisms. Epilepsia. 2005;46(6):858–77.PubMedGoogle Scholar
  87. Schousboe A, Larsson OM, Wood JD, Krogsgaard-Larsen P. Transport and metabolism of gamma-­aminobutyric acid in neurons and glia: implications for epilepsy. Epilepsia. 1983;24:531–8.PubMedGoogle Scholar
  88. Schwarzer C, Tsunashima K, Wanzenböck C, Fuchs K, Sieghart W, Sperk G. GABAA receptor subunits in the rat hippocampus II: altered distribution in kainic acid-induced temporal lobe epilepsy. Neuroscience. 1997;80:1001–17.PubMedGoogle Scholar
  89. Scimemi A, Semyanov A, Sperk G, Kullmann DM, Walker MC. Multiple and plastic receptors mediate tonic GABAA receptor currents in the hippocampus. J Neurosci. 2005;25:10016–24.PubMedGoogle Scholar
  90. Sommer B, Poustka A, Spurr NK, Seeburg PH, et al. The murine GABAA receptor delta-subunit gene: structure and assignment to human chromosome 1. DNA Cell Biol. 1990;9:561–8.PubMedGoogle Scholar
  91. Sperk G, Drexel M, Pirker S. Neuronal plasticity in animal models and the epileptic human hippocampus. Epilepsia. 2009;50:29–31.PubMedGoogle Scholar
  92. Stell BM, Brickley SG, Tang CY, Farrant M, Mody I. Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by delta subunit-containing GABAA receptors. Proc Natl Acad Sci U S A. 2003;100:14439–44.PubMedGoogle Scholar
  93. Tanaka M, Olsen RW, Medina MT, Schwartz E, Alonso ME, Duron RM, et al. Hyperglycosylation and reduced GABA currents of mutated GABRB3 polypeptide in remitting childhood absence epilepsy. Am J Hum Genet. 2008;82:1249–61.PubMedGoogle Scholar
  94. Tapia R. Biochemical pharmacology of GABA in CNS. In: Iversen LL, Iversen SD, Snyder SH, editors. Handbook of psychopharmacology. New York: Plenum Publishing Corporation; 1975.Google Scholar
  95. Tapia R, Pasantes H. Relationships between pyridoxal phosphate availability, activity of vitamin B 6 -dependent enzymes and convulsions. Brain Res. 1971;29:111–22.PubMedGoogle Scholar
  96. Ulrich D, Bettler B. GABA(B) receptors: synaptic functions and mechanisms of diversity. Curr Opin Neurobiol. 2007;17:298–303.PubMedGoogle Scholar
  97. Urak L, Feucht M, Fathi N, Hornik K, Fuchs K, et al. A GABRB3 promoter haplotype associated with childhood absence epilepsy impairs transcriptional activity. Hum Mol Genet. 2006;15:2533–41.PubMedGoogle Scholar
  98. Wagstaff J, Chaillet JR, Lalande M. The GABAA receptor beta 3 subunit gene: characterization of a human cDNA from chromosome 15q11q13 and mapping to a region of conserved synteny on mouse chromosome 7. Genomics. 1991;11:1071–8.PubMedGoogle Scholar
  99. Wallace RH, Marini C, Petrou S, Harkin LA, Bowser DN, Panchai RG, et al. Mutant GABA(A) receptor gamma-2-subunit in childhood absence epilepsy and febrile seizures. Nat Genet. 2001;28:49–52.PubMedGoogle Scholar
  100. Walls AB, Nilsen LH, Eyjolfsson EM, et al. GAD65 is essential for synthesis of GABA destined for tonic inhibition regulating epileptiform activity. J Neurochem. 2010;115:1398–408.PubMedGoogle Scholar
  101. Walls AB, Eyjolfsson EM, Smeland OB,Vestergaard HT, Hansen SL, Schousboe, et al. Knockout of GAD65 has major impact on synaptic GABA synthesized from astrocyte-derived glutamine. J Cereb Blood Flow Metab. 2011;31:494–503.PubMedGoogle Scholar
  102. Wang XJ, Buzsaki G. Gamma oscillation by synaptic inhibition in hippocampal interneuronal network model. J Neurosci. 1996;16:6402–13.PubMedGoogle Scholar
  103. Wang DD, Kriegstein AR. Blocking early GABA depolarization with bumetanide results in permanent alterations in cortical circuits and sensorimotor gating deficits. Cereb Cortex. 2010;21:574–87.PubMedGoogle Scholar
  104. Wang X, Sun W, Zhu X, Li L, Wu X, Lin H, et al. Association between the gamma-aminobutyric acid type B receptor 1 and 2 gene polymorphisms and mesial temporal lobe epilepsy in a Han Chinese population. Epilepsy Res. 2008;81:198–203.PubMedGoogle Scholar
  105. Watanabe M, Maemura K, Kanbara K, Tamayama T, Hayasaki H. GABA and GABA receptors in the central nervous system and other organs. In: Jeon KW, editor. A survey of cell biology. San Diego, CA: Academic; 2002.Google Scholar
  106. Wieland HA, Luddens H, Seeburg PH. A single histidine in GABAA receptors is essential for benzodiazepine agonist binding. J Biol Chem. 1992;267:1426–9.PubMedGoogle Scholar
  107. Wilcox AS, Warrington JA, Gardiner K, et al. Human chromosomal localization of genes encoding the gamma 1 and gamma 2 subunits of the gamma-aminobutyric acid receptor indicates that members of this gene family are often clustered in the genome. Proc Natl Acad Sci U S A. 1992;89:5857–61.PubMedGoogle Scholar
  108. Wohlfarth KM, Bianchi MT, Macdonald RL. Enhanced neurosteroid potentiation of ternary GABAA receptors containing the δ subunit. J Neurosci. 2002;22:1541–9.PubMedGoogle Scholar
  109. Zhan RZ, Nadler JV. Enhanced tonic GABA current in normotopic and hilar ectopic dentate granule cells after pilocarpine-induced status epilepticus. J Neurophysiol. 2009;102:670–81.PubMedGoogle Scholar
  110. Zhang N, Wei W, Mody I, Houser CR. Altered localization of GABAA receptor subunits on dentate granule cell dendrites influences tonic and phasic inhibition in a mouse model of epilepsy. J Neurosci. 2007;27:7520–31.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2013

Authors and Affiliations

  • Sandra Orozco-Suárez
    • 1
  • David Escalante-Santiago
    • 1
  • Iris Angélica Feria-Romero
    • 1
  • Monica E. Ureña-Guerrero
    • 2
  • Luisa Rocha
    • 3
  • Mario A. Alonso-Vanegas
    • 4
  • Juana Villeda-Hernandez
    • 5
  • Ana Luisa Velasco
    • 6
  1. 1.Medical Research Unit in Neurological DiseasesNational Medical Center, “Siglo XXI”, IMSS Hospital of SpecialitiesMexico CityMexico
  2. 2.Departamento de Biología Celular y Molecular, Centro Universitario de Ciencias Biológicas y AgropecuariasUniversidad de GuadalajaraZapopanMexico
  3. 3.Department of PharmacobiologyCenter for Research and Advanced StudiesMexico CityMexico
  4. 4.ABC Hospital, Santa Fé, Neurology Center, and National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”Mexico CityMexico
  5. 5.Pathology DepartmentNational Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”Mexico CityMexico
  6. 6.Department of Neurology and NeurosurgeryGeneral Hospital of MexicoMexico CityMexico

Personalised recommendations