Skip to main content
SpringerLink
Log in

Is Plasticity of GABAergic Mechanisms Relevant to Epileptogenesis?

  • Chapter
  • First Online:
Issues in Clinical Epileptology: A View from the Bench

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 813))

Abstract

Numerous changes in GABAergic neurons, receptors, and inhibitory mechanisms have been described in temporal lobe epilepsy (TLE), either in humans or in animal models. Nevertheless, there remains a common assumption that epilepsy can be explained by simply an insufficiency of GABAergic inhibition. Alternatively, investigators have suggested that there is hyperinhibition that masks an underlying hyperexcitability. Here we examine the status epilepticus (SE) models of TLE and focus on the dentate gyrus of the hippocampus, where a great deal of data have been collected. The types of GABAergic neurons and GABAA receptors are summarized under normal conditions and after SE. The role of GABA in development and in adult neurogenesis is discussed. We suggest that instead of “too little or too much” GABA there is a complexity of changes after SE that makes the emergence of chronic seizures (epileptogenesis) difficult to understand mechanistically, and difficult to treat. We also suggest that this complexity arises, at least in part, because of the remarkable plasticity of GABAergic neurons and GABAA receptors in response to insult or injury.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Acsady L, Kamondi A, Sik A, Freund T, Buzsaki G (1998) GABAergic cells are the major postsynaptic targets of mossy fibers in the rat hippocampus. J Neurosci 18:3386–3403

    CAS  PubMed  Google Scholar 

  2. Amaral DG, Scharfman HE, Lavenex P (2007) The dentate gyrus: fundamental neuroanatomical organization (dentate gyrus for dummies). Prog Brain Res 163:3–22

    PubMed Central  PubMed  Google Scholar 

  3. Armstrong C, Krook-Magnuson E, Soltesz I (2012) Neurogliaform and ivy cells: a major family of nNOS expressing GABAergic neurons. Front Neural Circuit 6:23

    CAS  Google Scholar 

  4. Baulac S, Huberfeld G, Gourfinkel-An I, Mitropoulou G, Beranger A, Prud’homme JF, Baulac M, Brice A, Bruzzone R, LeGuern E (2001) First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the γ2-subunit gene. Nat Genet 28:46–48

    CAS  PubMed  Google Scholar 

  5. Bausch SB (2005) Axonal sprouting of GABAergic interneurons in temporal lobe epilepsy. Epilepsy Behav 7:390–400

    PubMed  Google Scholar 

  6. Bekenstein JW, Lothman EW (1993) Dormancy of inhibitory interneurons in a model of temporal lobe epilepsy. Science 259:97–100

    CAS  PubMed  Google Scholar 

  7. Ben-Ari Y (2002) Excitatory actions of GABA during development: the nature of the nurture. Nat Rev Neurosci 3:728–739

    CAS  PubMed  Google Scholar 

  8. Ben-Ari Y, Khalilov I, Kahle KT, Cherubini E (2012) The GABA excitatory/inhibitory shift in brain maturation and neurological disorders. Neuroscientist 18:467–486

    CAS  PubMed  Google Scholar 

  9. Ben-Ari Y, Woodin MA, Sernagor E, Cancedda L, Vinay L, Rivera C, Legendre P, Luhmann HJ, Bordey A, Wenner P, Fukuda A, van den Pol AN, Gaiarsa JL, Cherubini E (2012) Refuting the challenges of the developmental shift of polarity of GABA actions: GABA more exciting than ever! Front Cell Neurosci 6:35

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Bengzon J, Kokaia Z, Elmer E, Nanobashvili A, Kokaia M, Lindvall O (1997) Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures. Proc Natl Acad Sci U S A 94:10432–10437

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Bernard C, Cossart R, Hirsch JC, Esclapez M, Ben-Ari Y (2000) What is GABAergic inhibition? How is it modified in epilepsy? Epilepsia 41(Suppl 6):S90–S95

    PubMed  Google Scholar 

  12. Bernard C, Esclapez M, Hirsch JC, Ben-Ari Y (1998) Interneurones are not so dormant in temporal lobe epilepsy: a critical reappraisal of the dormant basket cell hypothesis. Epilepsy Res 32:93–103

    CAS  PubMed  Google Scholar 

  13. Blair RE, Sombati S, Lawrence DC, McCay BD, DeLorenzo RJ (2004) Epileptogenesis causes acute and chronic increases in GABA(A) receptor endocytosis that contributes to the induction and maintenance of seizures in the hippocampal culture model of acquired epilepsy. J Pharmacol Exp Ther 310:871–880

    CAS  PubMed  Google Scholar 

  14. Bowery NG (2010) Historical perspective and emergence of the GABAB receptor. Adv Pharmacol 58:1–18

    CAS  PubMed  Google Scholar 

  15. Bregestovski P, Bernard C (2012) Excitatory GABA: how a correct observation may turn out to be an experimental artifact. Front Pharmacol 3:65

    PubMed Central  PubMed  Google Scholar 

  16. Brooks-Kayal AR, Bath KG, Berg AT, Galanopoulou AS, Holmes GL, Jensen FE, Kanner AM, O’Brien TJ, Whittemore VH, Winawer MR, Patel M, Scharfman HE (2013) Issues related to symptomatic and disease-modifying treatments affecting cognitive and neuropsychiatric comorbidities of epilepsy. Epilepsia 54(Suppl 4):44–60

    PubMed Central  PubMed  Google Scholar 

  17. Brooks-Kayal AR, Shumate MD, Jin H, Lin DD, Rikhter TY, Holloway KL, Coulter DA (1999) Human neuronal γ-aminobutyric acida receptors: coordinated subunit mRNA expression and functional correlates in individual dentate granule cells. J Neurosci 19:8312–8318

    CAS  PubMed  Google Scholar 

  18. Brooks-Kayal AR, Shumate MD, Jin H, Rikhter TY, Coulter DA (1998) Selective changes in single cell GABA(A) receptor subunit expression and function in temporal lobe epilepsy. Nat Med 4:1166–1172

    CAS  PubMed  Google Scholar 

  19. Buckmaster PS (2012) Mossy fiber sprouting in the dentate gyrus. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV (eds) Jasper’s basic mechanisms of the epilepsies, 4th edn. Oxford, New York, pp 416–431

    Google Scholar 

  20. Buckmaster PS, Zhang GF, Yamawaki R (2002) Axon sprouting in a model of temporal lobe epilepsy creates a predominantly excitatory feedback circuit. J Neurosci 22:6650–6658

    CAS  PubMed  Google Scholar 

  21. Buhl E, Otis T, Mody I (1996) Zinc-induced collapse of augmented inhibition by GABA in a temporal lobe epilepsy model. Science 271:369–373

    CAS  PubMed  Google Scholar 

  22. Buhl EH, Han ZS, Lorinczi Z, Stezhka VV, Karnup SV, Somogyi P (1994) Physiological properties of anatomically identified axo-axonic cells in the rat hippocampus. J Neurophysiol 71:1289–1307

    CAS  PubMed  Google Scholar 

  23. Caiati MD (2013) Is GABA co-released with glutamate from hippocampal mossy fiber terminals? J Neurosci 33:1755–1756

    CAS  PubMed  Google Scholar 

  24. Cancedda L, Fiumelli H, Chen K, Poo MM (2007) Excitatory GABA action is essential for morphological maturation of cortical neurons in vivo. J Neurosci 27:5224–5235

    CAS  PubMed  Google Scholar 

  25. Chavkin C (2000) Dynorphins are endogenous opioid peptides released from granule cells to act neurohumorly and inhibit excitatory neurotransmission in the hippocampus. Prog Brain Res 125:363–367

    CAS  PubMed  Google Scholar 

  26. Chen JW, Naylor DE, Wasterlain CG (2007) Advances in the pathophysiology of status epilepticus. Acta Neurol Scand Suppl. 186:7–15

    Google Scholar 

  27. Cherubini E, Griguoli M, Safiulina V, Lagostena L (2011) The depolarizing action of GABA controls early network activity in the developing hippocampus. Mol Neurobiol 43:97–106

    CAS  PubMed  Google Scholar 

  28. Chittajallu R, Kunze A, Mangin JM, Gallo V (2007) Differential synaptic integration of interneurons in the outer and inner molecular layers of the developing dentate gyrus. J Neurosci 27:8219–8225

    CAS  PubMed  Google Scholar 

  29. Choi YS, Lin SL, Lee B, Kurup P, Cho HY, Naegele JR, Lombroso PJ, Obrietan K (2007) Status epilepticus-induced somatostatinergic hilar interneuron degeneration is regulated by striatal enriched protein tyrosine phosphatase. J Neurosci 27:2999–3009

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Cohen AS, Lin DD, Quirk GL, Coulter DA (2003) Dentate granule cell GABA(A) receptors in epileptic hippocampus: enhanced synaptic efficacy and altered pharmacology. Eur J Neurosci 17:1607–1616

    PubMed Central  PubMed  Google Scholar 

  31. Curia G, Longo D, Biagini G, Jones RS, Avoli M (2008) The pilocarpine model of temporal lobe epilepsy. J Neurosci Methods 172:143–157

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Davenport CJ, Brown WJ, Babb TL (1990) GABAergic neurons are spared after intrahippocampal kainate in the rat. Epilepsy Res 5:28–42

    CAS  PubMed  Google Scholar 

  33. DeFelipe J (1999) Chandelier cells and epilepsy. Brain 122(Pt 10):1807–1822

    PubMed  Google Scholar 

  34. Deller T (1998) The anatomical organization of the rat fascia dentata: new aspects of laminar organization as revealed by anterograde tracing with phaseolus vulgaris-luecoagglutinin (PHAL). Anat Embryol (Berl) 197:89–103

    CAS  Google Scholar 

  35. Deller T, Leranth C (1990) Synaptic connections of neuropeptide Y (NPY) immunoreactive neurons in the hilar area of the rat hippocampus. J Comp Neurol 300:433–447

    CAS  PubMed  Google Scholar 

  36. Dieni CV, Chancey JH, Overstreet-Wadiche LS (2012) Dynamic functions of GABA signaling during granule cell maturation. Front Neural Circuits 6:113

    PubMed Central  PubMed  Google Scholar 

  37. Dougherty KD, Milner TA (1999) Cholinergic septal afferent terminals preferentially contact neuropeptide Y-containing interneurons compared to parvalbumin-containing interneurons in the rat dentate gyrus. J Neurosci 19:10140–10152

    CAS  PubMed  Google Scholar 

  38. Dougherty KD, Milner TA (1999) P75ntr immunoreactivity in the rat dentate gyrus is mostly within presynaptic profiles but is also found in some astrocytic and postsynaptic profiles. J Comp Neurol 407:77–91

    CAS  PubMed  Google Scholar 

  39. Franck JE, Pokorny J, Kunkel DD, Schwartzkroin PA (1995) Physiologic and morphologic characteristics of granule cell circuitry in human epileptic hippocampus. Epilepsia 36:543–558

    CAS  PubMed  Google Scholar 

  40. Frazier CJ (2007) Endocannabinoids in the dentate gyrus. Prog Brain Res 163:319–337

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Freund TF (1992) Gabaergic septal and serotonergic median raphe afferents preferentially innervate inhibitory interneurons in the hippocampus and dentate gyrus. Epilepsy Res Suppl 7:79–91

    CAS  PubMed  Google Scholar 

  42. Freund TF, Buzsaki G (1996) Interneurons of the hippocampus. Hippocampus 6:347–470

    CAS  PubMed  Google Scholar 

  43. Frotscher M, Jonas P, Sloviter RS (2006) Synapses formed by normal and abnormal hippocampal mossy fibers. Cell Tissue Res 326:361–367

    PubMed  Google Scholar 

  44. Fu LY, van den Pol AN (2007) Gaba excitation in mouse hilar neuropeptide Y neurons. J Physiol 579:445–464

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Gibbs J, Shumate M, Coulter D (1997) Differential epilepsy-associated alterations in postsynaptic GABAA receptor function in dentate granule and ca1 neurons. J Neurophysiol 77:1924–1938

    CAS  PubMed  Google Scholar 

  46. Gonzalez MI, Brooks-Kayal A (2011) Altered GABA(A) receptor expression during epileptogenesis. Neurosci Lett 497:218–222

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Goodkin HP, Joshi S, Mtchedlishvili Z, Brar J, Kapur J (2008) Subunit-specific trafficking of GABA(A) receptors during status epilepticus. J Neurosci 28:2527–2538

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Goodkin HP, Yeh JL, Kapur J (2005) Status epilepticus increases the intracellular accumulation of GABA(A) receptors. J Neurosci 25:5511–5520

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Goodman JH, Sloviter RS (1992) Evidence for commissurally projecting parvalbumin-immunoreactive basket cells in the dentate gyrus of the rat. Hippocampus 2:13–21

    CAS  PubMed  Google Scholar 

  50. Gutierrez R, Heinemann U (2006) Co-existence of GABA and Glu in the hippocampal granule cells: implications for epilepsy. Curr Top Med Chem 6:975–978

    CAS  PubMed  Google Scholar 

  51. Halasy K, Somogyi P (1993) Subdivisions in the multiple GABAergic innervation of granule cells in the dentate gyrus of the rat hippocampus. Eur J Neurosci 5:411–429

    CAS  PubMed  Google Scholar 

  52. Han ZS, Buhl EH, Lorinczi Z, Somogyi P (1993) A high degree of spatial selectivity in the axonal and dendritic domains of physiologically identified local-circuit neurons in the dentate gyrus of the rat hippocampus. Eur J Neurosci 5:395–410

    CAS  PubMed  Google Scholar 

  53. Henze DA, Buzsaki G (2007) Hilar mossy cells: functional identification and activity in vivo. Prog Brain Res 163:199–216

    PubMed  Google Scholar 

  54. Houser CR (1991) GABA neurons in seizure disorders: a review of immunocytochemical studies. Neurochem Res 16:295–308

    CAS  PubMed  Google Scholar 

  55. Houser CR (2007) Interneurons of the dentate gyrus: an overview of cell types, terminal fields and neurochemical identity. Prog Brain Res 163:217–232

    CAS  PubMed  Google Scholar 

  56. Houser CR, Harris AB, Vaughn JE (1986) Time course of the reduction of GABA terminals in a model of focal epilepsy: a glutamic acid decarboxylase immunocytochemical study. Brain Res 383:129–145

    CAS  PubMed  Google Scholar 

  57. Hu Y, Russek SJ (2008) BDNF and the diseased nervous system: a delicate balance between adaptive and pathological processes of gene regulation. J Neurochem 105:1–17

    CAS  PubMed  Google Scholar 

  58. Huguenard JR (1999) Neuronal circuitry of thalamocortical epilepsy and mechanisms of antiabsence drug action. Adv Neurol 79:991–999

    CAS  PubMed  Google Scholar 

  59. Jacob TC, Moss SJ, Jurd R (2008) GABA(A) receptor trafficking and its role in the dynamic modulation of neuronal inhibition. Nat Rev Neurosci 9:331–343

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Jaffe DB, Gutierrez R (2007) Mossy fiber synaptic transmission: communication from the dentate gyrus to area ca3. Prog Brain Res 163:109–132

    CAS  PubMed  Google Scholar 

  61. Jakubs K, Nanobashvili A, Bonde S, Ekdahl CT, Kokaia Z, Kokaia M, Lindvall O (2006) Environment matters: synaptic properties of neurons born in the epileptic adult brain develop to reduce excitability. Neuron 52:1047–1059

    CAS  PubMed  Google Scholar 

  62. Jessberger S, Zhao C, Toni N, Clemenson GD Jr, Li Y, Gage FH (2007) Seizure-associated, aberrant neurogenesis in adult rats characterized with retrovirus-mediated cell labeling. J Neurosci 27:9400–9407

    CAS  PubMed  Google Scholar 

  63. Jung KH, Chu K, Kim M, Jeong SW, Song YM, Lee ST, Kim JY, Lee SK, Roh JK (2004) Continuous cytosine-b-D-arabinofuranoside infusion reduces ectopic granule cells in adult rat hippocampus with attenuation of spontaneous recurrent seizures following pilocarpine-induced status epilepticus. Eur J Neurosci 19:3219–3226

    PubMed  Google Scholar 

  64. Kahle KT, Staley KJ (2008) The bumetanide-sensitive Na-K-2Cl cotransporter NKCC1 as a potential target of a novel mechanism-based treatment strategy for neonatal seizures. Neurosurg Focus 25:E22

    PubMed  Google Scholar 

  65. Kahle KT, Staley KJ (2012) Neonatal seizures and neuronal transmembrane ion transport. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV (eds) Jasper’s basic mechanisms of the epilepsies, 4th edn. Oxford, New York, pp 1066–1076

    Google Scholar 

  66. Kanner AM (2013) Epilepsy, depression and anxiety disorders: a complex relation with significant therapeutic implications for the three conditions. J Neurol Neurosurg Psychiatry 84:e1

    Google Scholar 

  67. Kempermann G (2006) Adult neurogenesis. Oxford University Press, Oxford

    Google Scholar 

  68. Koyama R, Tao K, Sasaki T, Ichikawa J, Miyamoto D, Muramatsu R, Matsuki N, Ikegaya Y (2012) GABAergic excitation after febrile seizures induces ectopic granule cells and adult epilepsy. Nat Med 18:1271–1278

    CAS  PubMed  Google Scholar 

  69. Kron MM, Zhang H, Parent JM (2010) The developmental stage of dentate granule cells dictates their contribution to seizure-induced plasticity. J Neurosci 30:2051–2059

    CAS  PubMed  Google Scholar 

  70. Kullmann DM, Ruiz A, Rusakov DM, Scott R, Semyanov A, Walker MC (2005) Presynaptic, extrasynaptic and axonal GABAA receptors in the CNS: where and why? Prog Biophys Mol Biol 87:33–46

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Lagrange AH, Botzolakis EJ, Macdonald RL (2007) Enhanced macroscopic desensitization shapes the response of α4 subtype-containing GABAA receptors to synaptic and extrasynaptic GABA. J Physiol 578:655–676

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Lauren HB, Pitkanen A, Nissinen J, Soini SL, Korpi ER, Holopainen IE (2003) Selective changes in γ-aminobutyric acid type a receptor subunits in the hippocampus in spontaneously seizing rats with chronic temporal lobe epilepsy. Neurosci Lett 349:58–62

    CAS  PubMed  Google Scholar 

  73. Laurie DJ, Wisden W, Seeburg PH (1992) The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. Iii. Embryonic and postnatal development. J Neurosci 12:4151–4172

    CAS  PubMed  Google Scholar 

  74. Leranth C, Hajszan T (2007) Extrinsic afferent systems to the dentate gyrus. Prog Brain Res 163:63–84

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Lothman EW, Bertram EH 3rd, Kapur J, Bekenstein JW (1996) Temporal lobe epilepsy: studies in a rat model showing dormancy of GABAergic inhibitory interneurons. Epilepsy Res Suppl 12:145–156

    CAS  PubMed  Google Scholar 

  76. Lund IV, Hu Y, Raol YH, Benham RS, Faris R, Russek SJ, Brooks-Kayal AR (2008) BDNF selectively regulates GABAA receptor transcription by activation of the JAK/STAT pathway. Sci Signal 1:ra9

    PubMed Central  PubMed  Google Scholar 

  77. Macdonald RL, Olsen RW (1994) GABAA receptor channels. Annu Rev Neurosci 17:569–602

    CAS  PubMed  Google Scholar 

  78. Magloczky Z, Freund TF (2005) Impaired and repaired inhibitory circuits in the epileptic human hippocampus. Trends Neurosci 28:334–340

    CAS  PubMed  Google Scholar 

  79. McCloskey DP, Hintz TM, Pierce JP, Scharfman HE (2006) Stereological methods reveal the robust size and stability of ectopic hilar granule cells after pilocarpine-induced status epilepticus in the adult rat. Eur J Neurosci 24:2203–2210

    PubMed Central  PubMed  Google Scholar 

  80. Milner TA, Veznedaroglu E (1992) Ultrastructural localization of neuropeptide Y-like immunoreactivity in the rat hippocampal formation. Hippocampus 2:107–125

    CAS  PubMed  Google Scholar 

  81. Morgan RJ, Santhakumar V, Soltesz I (2007) Modeling the dentate gyrus. Prog Brain Res 163:639–658

    PubMed  Google Scholar 

  82. Mori M, Gahwiler BH, Gerber U (2007) Recruitment of an inhibitory hippocampal network after bursting in a single granule cell. Proc Natl Acad Sci U S A 104:7640–7645

    CAS  PubMed Central  PubMed  Google Scholar 

  83. Moss SJ, Smart TG (1996) Modulation of amino acid-gated ion channels by protein phosphorylation. Int Rev Neurobiol 39:1–52

    CAS  PubMed  Google Scholar 

  84. Mott DD, Lewis DV (1994) The pharmacology and function of central GABAB receptors. Int Rev Neurobiol 36:97–223

    Google Scholar 

  85. Nadler JV, Perry BW, Cotman CW (1978) Intraventricular kainic acid preferentially destroys hippocampal pyramidal cells. Nature 271:676–677

    CAS  PubMed  Google Scholar 

  86. Naylor DE, Liu H, Wasterlain CG (2005) Trafficking of GABA(A) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus. J Neurosci 25:7724–7733

    CAS  PubMed  Google Scholar 

  87. Nusser Z, Mody I (2002) Selective modulation of tonic and phasic inhibitions in dentate gyrus granule cells. J Neurophysiol 87:2624–2628

    CAS  PubMed  Google Scholar 

  88. Olsen RW (1981) The GABA postsynaptic membrane receptor-ionophore complex. Site of action of convulsant and anticonvulsant drugs. Mol Cell Biochem 39:261–279

    CAS  PubMed  Google Scholar 

  89. Paredes MF, Greenwood J, Baraban SC (2003) Neuropeptide Y modulates a g protein-coupled inwardly rectifying potassium current in the mouse hippocampus. Neurosci Lett 340:9–12

    CAS  PubMed  Google Scholar 

  90. Parent JM, Yu TW, Leibowitz RT, Geschwind DH, Sloviter RS, Lowenstein DH (1997) Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci 17:3727–3738

    CAS  PubMed  Google Scholar 

  91. Pathak HR, Weissinger F, Terunuma M, Carlson GC, Hsu FC, Moss SJ, Coulter DA (2007) Disrupted dentate granule cell chloride regulation enhances synaptic excitability during development of temporal lobe epilepsy. J Neurosci 27:14012–14022

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Peng Z, Huang CS, Stell BM, Mody I, Houser CR (2004) Altered expression of the delta subunit of the GABAA receptor in a mouse model of temporal lobe epilepsy. J Neurosci 24:8629–8639

    CAS  PubMed  Google Scholar 

  93. Peterson GM, Ribak CE (1987) Hippocampus of the seizure-sensitive gerbil is a specific site for anatomical changes in the GABAergic system. J Comp Neurol 261:405–422

    CAS  PubMed  Google Scholar 

  94. Pierce JP, McCloskey DP, Scharfman HE (2011) Morphometry of hilar ectopic granule cells in the rat. J Comp Neurol 519:1196–1218

    PubMed Central  PubMed  Google Scholar 

  95. Pitkanen A, Moshe s, Schwartzkroin PA (2006) Models of seizures and epilepsy. Elsevier, New York

    Google Scholar 

  96. Porter BE, Maronski M, Brooks-Kayal AR (2004) Fate of newborn dentate granule cells after early life status epilepticus. Epilepsia 45:13–19

    PubMed  Google Scholar 

  97. Pritchett D, Sontheimer H, Shivers B, Ymer S, Kellenmann H, Schofield P, Seeburg P (1989) Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology. Nature 338:582–585

    CAS  PubMed  Google Scholar 

  98. Pun RY, Rolle IJ, Lasarge CL, Hosford BE, Rosen JM, Uhl JD, Schmeltzer SN, Faulkner C, Bronson SL, Murphy BL, Richards DA, Holland KD, Danzer SC (2012) Excessive activation of mTOR in postnatally generated granule cells is sufficient to cause epilepsy. Neuron 75:1022–1034

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Raol YH, Lund IV, Bandyopadhyay S, Zhang G, Roberts DS, Wolfe JH, Russek SJ, Brooks-Kayal AR (2006) Enhancing GABA(A) receptor α 1 subunit levels in hippocampal dentate gyrus inhibits epilepsy development in an animal model of temporal lobe epilepsy. J Neurosci 26:11342–11346

    CAS  PubMed  Google Scholar 

  100. Ribak CE (1985) Axon terminals of GABAergic chandelier cells are lost at epileptic foci. Brain Res 326:251–260

    CAS  PubMed  Google Scholar 

  101. Ribak CE, Harris AB, Vaughn JE, Roberts E (1979) Inhibitory, GABAergic nerve terminals decrease at sites of focal epilepsy. Science 205:211–214

    CAS  PubMed  Google Scholar 

  102. Ribak CE, Hunt CA, Bakay RA, Oertel WH (1986) A decrease in the number of GABAergic somata is associated with the preferential loss of GABAergic terminals at epileptic foci. Brain Res 363:78–90

    CAS  PubMed  Google Scholar 

  103. Ribak CE, Joubran C, Kesslak JP, Bakay RA (1989) A selective decrease in the number of GABAergic somata occurs in pre-seizing monkeys with alumina gel granuloma. Epilepsy Res 4:126–138

    CAS  PubMed  Google Scholar 

  104. Ribak CE, Shapiro LA, Yan XX, Dashtipour K, Nadler JV, Obenaus A, Spigelman I, Buckmaster PS (2012) Seizure-induced formation of basal dendrites on granule cells of the rodent dentate gyrus. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV (eds) Jasper’s basic mechanisms of the epilepsies, 4th edn. National Center for Biotechnology Information, Bethesda

    Google Scholar 

  105. Riccio A, Alvania RS, Lonze BE, Ramanan N, Kim T, Huang Y, Dawson TM, Snyder SH, Ginty DD (2006) A nitric oxide signaling pathway controls CREB-mediated gene expression in neurons. Mol Cell 21:283–294

    CAS  PubMed  Google Scholar 

  106. Rivera C, Voipio J, Payne JA, Ruusuvuori E, Lahtinen H, Lamsa K, Pirvola U, Saarma M, Kaila K (1999) The K+/Cl– co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 397:251–255

    Google Scholar 

  107. Roberts DS, Hu Y, Lund IV, Brooks-Kayal AR, Russek SJ (2006) Brain-derived neurotrophic factor (BDNF)-induced synthesis of early growth response factor 3 (Egr3) controls the levels of type A GABA receptor α4 subunits in hippocampal neurons. J Biol Chem 281:29431–29435

    CAS  PubMed  Google Scholar 

  108. Roberts DS, Raol YH, Bandyopadhyay S, Lund IV, Budreck EC, Passini MA, Wolfe JH, Brooks-Kayal AR, Russek SJ (2005) Egr3 stimulation of gabra4 promoter activity as a mechanism for seizure-induced up-regulation of GABA(A) receptor α4 subunit expression. Proc Natl Acad Sci U S A 102:11894–11899

    CAS  PubMed Central  PubMed  Google Scholar 

  109. Roberts E (1986) Failure of GABAergic inhibition: a key to local and global seizures. Adv Neurol 44:319–341

    CAS  PubMed  Google Scholar 

  110. Roberts RC, Ribak CE, Oertel WH (1985) Increased numbers of GABAergic neurons occur in the inferior colliculus of an audiogenic model of genetic epilepsy. Brain Res 361:324–338

    CAS  PubMed  Google Scholar 

  111. Rudolph U, Mohler H (2006) Gaba-based therapeutic approaches: GABAA receptor subtype functions. Curr Opin Pharmacol 6:18–23

    CAS  PubMed  Google Scholar 

  112. Sahay A, Hen R (2008) Hippocampal neurogenesis and depression. Novartis Found Symp 289:152–160; discussion 60–64, 93–95

    CAS  PubMed  Google Scholar 

  113. Santhakumar V, Bender R, Frotscher M, Ross ST, Hollrigel GS, Toth Z, Soltesz I (2000) Granule cell hyperexcitability in the early post-traumatic rat dentate gyrus: the ‘irritable mossy cell’ hypothesis. J Physiol 524(Pt 1):117–134

    CAS  PubMed Central  PubMed  Google Scholar 

  114. Santhakumar V, Ratzliff AD, Jeng J, Toth Z, Soltesz I (2001) Long-term hyperexcitability in the hippocampus after experimental head trauma. Ann Neurol 50:708–717

    CAS  PubMed  Google Scholar 

  115. Scharfman HE (1995) Electrophysiological diversity of pyramidal-shaped neurons at the granule cell layer/hilus border of the rat dentate gyrus recorded in vitro. Hippocampus 5:287–305

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Scharfman HE (1999) The role of nonprincipal cells in dentate gyrus excitability and its relevance to animal models of epilepsy and temporal lobe epilepsy. Adv Neurol 79:805–820

    CAS  PubMed  Google Scholar 

  117. Scharfman HE (2004) Functional implications of seizure-induced neurogenesis. Adv Exp Med Biol 548:192–212

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Scharfman HE, Sollas AE, Berger RE, Goodman JH, Pierce JP (2003) Perforant path activation of ectopic granule cells that are born after pilocarpine-induced seizures. Neuroscience 121:1017–1029

    Google Scholar 

  119. Scharfman HE, Goodman JH, Sollas AL (2000) Granule-like neurons at the hilar/CA3 border after status epilepticus and their synchrony with area CA3 pyramidal cells: functional implications of seizure-induced neurogenesis. J Neurosci 20:6144–6158

    CAS  PubMed  Google Scholar 

  120. Scharfman HE, Gray WP (2006) Plasticity of neuropeptide y in the dentate gyrus after seizures, and its relevance to seizure-induced neurogenesis. EXS: 95:193–211

    Google Scholar 

  121. Scharfman HE, Gray WP (2007) Relevance of seizure-induced neurogenesis in animal models of epilepsy to the etiology of temporal lobe epilepsy. Epilepsia 48(Suppl 2):33–41

    PubMed Central  PubMed  Google Scholar 

  122. Scharfman HE, Kunkel DD, Schwartzkroin PA (1990) Synaptic connections of dentate granule cells and hilar neurons: results of paired intracellular recordings and intracellular horseradish peroxidase injections. Neuroscience 37:693–707

    CAS  PubMed  Google Scholar 

  123. Scharfman HE, Maclusky NJ (2014) Differential regulation of BDNF, synaptic plasticity and sprouting in the hippocampal mossy fiber pathway of male and female rats. Neuropharmacology 76:696–708

    CAS  PubMed  Google Scholar 

  124. Scharfman HE, McCloskey DP (2009) Postnatal neurogenesis as a therapeutic target in temporal lobe epilepsy. Epilepsy Res 85:150–161

    CAS  PubMed Central  PubMed  Google Scholar 

  125. Scharfman HE, Mercurio TC, Goodman JH, Wilson MA, MacLusky NJ (2003) Hippocampal excitability increases during the estrous cycle in the rat: a potential role for brain-derived neurotrophic factor. J Neurosci 23:11641–11652

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Scharfman HE, Myers CE (2012) Hilar mossy cells of the dentate gyrus: a historical perspective. Front Neural Circuits 6:106

    PubMed Central  PubMed  Google Scholar 

  127. Scharfman HE, Pedley TA (2006) Temporal lobe epilepsy. In: Gilman S (ed) The neurobiology of disease. Academic, New York

    Google Scholar 

  128. Scharfman HE, Smith KL, Goodman JH, Sollas AL (2001) Survival of dentate hilar mossy cells after pilocarpine-induced seizures and their synchronized burst discharges with area CA3 pyramidal cells. Neuroscience 104:741–759

    CAS  PubMed Central  PubMed  Google Scholar 

  129. Scharfman HE, Sollas AL, Berger RE, Goodman JH (2003) Electrophysiological evidence of monosynaptic excitatory transmission between granule cells after seizure-induced mossy fiber sprouting. J Neurophysiol 90:2536–2547

    PubMed  Google Scholar 

  130. Scharfman HE, Sollas AL, Goodman JH (2002) Spontaneous recurrent seizures after pilocarpine-induced status epilepticus activate calbindin-immunoreactive hilar cells of the rat dentate gyrus. Neuroscience 111:71–81

    CAS  PubMed  Google Scholar 

  131. Schneiderman JH, Schwartzkroin PA (1982) Effects of phenytoin on normal activity and on penicillin-induced bursting in the guinea pig hippocampal slice. Neurology 32:730–738

    CAS  PubMed  Google Scholar 

  132. Schwartzkroin PA, Prince DA (1977) Penicillin-induced epileptiform activity in the hippocampal in vitro preparation. Ann Neurol 1:463–469

    CAS  PubMed  Google Scholar 

  133. Shapiro LA, Ribak CE, Jessberger S (2008) Structural changes for adult-born dentate granule cells after status epilepticus. Epilepsia 49(Suppl 5):13–18

    PubMed  Google Scholar 

  134. Sieghart W (2006) Structure, pharmacology, and function of GABAA receptor subtypes. Adv Pharmacol 54:231–263

    CAS  PubMed  Google Scholar 

  135. Sloviter RS (1987) Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy. Science 235:73–76

    CAS  PubMed  Google Scholar 

  136. Sloviter RS (1991) Permanently altered hippocampal structure, excitability, and inhibition after experimental status epilepticus in the rat: the “dormant basket cell” hypothesis and its possible relevance to temporal lobe epilepsy. Hippocampus 1:41–66

    CAS  PubMed  Google Scholar 

  137. Sloviter RS (1992) Possible functional consequences of synaptic reorganization in the dentate gyrus of kainate-treated rats. Neurosci Lett 137:91–96

    CAS  PubMed  Google Scholar 

  138. Sloviter RS, Nilaver G (1987) Immunocytochemical localization of gaba-, cholecystokinin-, vasoactive intestinal polypeptide-, and somatostatin-like immunoreactivity in the area dentata and hippocampus of the rat. J Comp Neurol 256:42–60

    CAS  PubMed  Google Scholar 

  139. Sloviter RS, Zappone CA, Harvey BD, Frotscher M (2006) Kainic acid-induced recurrent mossy fiber innervation of dentate gyrus inhibitory interneurons: possible anatomical substrate of granule cell hyper-inhibition in chronically epileptic rats. J Comp Neurol 494:944–960

    PubMed Central  PubMed  Google Scholar 

  140. Smith SS, Shen H, Gong QH, Zhou X (2007) Neurosteroid regulation of GABA(A) receptors: focus on the α4 and delta subunits. Pharmacol Ther 116:58–76

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Snead OC 3rd (1995) Basic mechanisms of generalized absence seizures. Ann Neurol 37:146–157

    PubMed  Google Scholar 

  142. Somogyi P, Freund TF, Hodgson AJ, Somogyi J, Beroukas D, Chubb IW (1985) Identified axo-axonic cells are immunoreactive for GABA in the hippocampus and visual cortex of the cat. Brain Res 332:143–149

    CAS  PubMed  Google Scholar 

  143. Sperk G, Drexel M, Pirker S (2009) Neuronal plasticity in animal models and the epileptic human hippocampus. Epilepsia 50:29–31

    PubMed Central  PubMed  Google Scholar 

  144. Sperk G, Furtinger S, Schwarzer C, Pirker S (2004) GABA and its receptors in epilepsy. Adv Exp Med Biol 548:92–103

    CAS  PubMed  Google Scholar 

  145. Sperk G, Hamilton T, Colmers WF (2007) Neuropeptide Y in the dentate gyrus. Prog Brain Res 163:285–297

    CAS  PubMed  Google Scholar 

  146. Sun C, Mtchedlishvili Z, Erisir A, Kapur J (2007) Diminished neurosteroid sensitivity of synaptic inhibition and altered location of the α4 subunit of GABA(A) receptors in an animal model of epilepsy. J Neurosci 27:12641–12650

    CAS  PubMed Central  PubMed  Google Scholar 

  147. Sutula TP, Dudek FE (2007) Unmasking recurrent excitation generated by mossy fiber sprouting in the epileptic dentate gyrus: an emergent property of a complex system. Prog Brain Res 163:541–563

    CAS  PubMed  Google Scholar 

  148. Swijsen A, Avila A, Brone B, Janssen D, Hoogland G, Rigo JM (2012) Experimental early-life febrile seizures induce changes in GABA(A)R-mediated neurotransmission in the dentate gyrus. Epilepsia 53:1968–1977

    CAS  PubMed  Google Scholar 

  149. Swijsen A, Brone B, Rigo JM, Hoogland G (2012) Long-lasting enhancement of GABA(A) receptor expression in newborn dentate granule cells after early-life febrile seizures. Dev Neurobiol 72:1516–1527

    CAS  PubMed  Google Scholar 

  150. Terunuma M, Xu J, Vithlani M, Sieghart W, Kittler J, Pangalos M, Haydon PG, Coulter DA, Moss SJ (2008) Deficits in phosphorylation of GABA(A) receptors by intimately associated protein kinase C activity underlie compromised synaptic inhibition during status epilepticus. J Neurosci 28:376–384

    CAS  PubMed Central  PubMed  Google Scholar 

  151. Thind KK, Yamawaki R, Phanwar I, Zhang G, Wen X, Buckmaster PS (2010) Initial loss but later excess of GABAergic synapses with dentate granule cells in a rat model of temporal lobe epilepsy. J Comp Neurol 518:647–667

    CAS  PubMed Central  PubMed  Google Scholar 

  152. Van Duijn H, Schwartzkroin PA, Prince DA (1973) Action of penicillin on inhibitory processes in the cat’s cortex. Brain Res 53:470–476

    PubMed  Google Scholar 

  153. Van Kempen TA, Kahlid S, Gonzalez AD, Spencer-Segal JL, Tsuda MC, Ogawa S, McEwen BS, Waters EM, Milner TA (2013) Sex and estrogen receptor expression influence opioid peptide levels in the mouse hippocampal mossy fiber pathway. Neurosci Lett 552:66–70

    PubMed  Google Scholar 

  154. Vicini S (1991) Pharmacologic significance of the structural heterogenetity of the GABAA receptor-chloride ion channel complex. Neuropsychopharmacology 4:9–15

    CAS  PubMed  Google Scholar 

  155. Vithlani M, Moss SJ (2009) The role of GABAAR phosphorylation in the construction of inhibitory synapses and the efficacy of neuronal inhibition. Biochem Soc Trans 37:1355–1358

    CAS  PubMed Central  PubMed  Google Scholar 

  156. von Kitzing E, Jonas P, Sakmann B (1994) Quantal analysis of excitatory postsynaptic currents at the hippocampal mossy fiber-CA3 pyramidal cell synapse. Adv Second Messenger Phosphoprotein Res 29:235–260

    Google Scholar 

  157. Waldbaum S, Dudek FE (2009) Single and repetitive paired-pulse suppression: a parametric analysis and assessment of usefulness in epilepsy research. Epilepsia 50:904–916

    PubMed Central  PubMed  Google Scholar 

  158. Walker MC, Ruiz A, Kullmann DM (2001) Monosynaptic GABAergic signaling from dentate to CA3 with a pharmacological and physiological profile typical of mossy fiber synapses. Neuron 29:703–715

    CAS  PubMed  Google Scholar 

  159. Wallace RH, Scheffer IE, Barnett S, Richards M, Dibbens L, Desai RR, Lerman-Sagie T, Lev D, Mazarib A, Brand N, Ben-Zeev B, Goikhman I, Singh R, Kremmidiotis G, Gardner A, Sutherland GR, George AL Jr, Mulley JC, Berkovic SF (2001) Neuronal sodium-channel α1-subunit mutations in generalized epilepsy with febrile seizures plus. Am J Hum Genet 68:859–865

    CAS  PubMed Central  PubMed  Google Scholar 

  160. Wang DD, Kriegstein AR (2009) Defining the role of GABA in cortical development. J Physiol 587:1873–1879

    CAS  PubMed Central  PubMed  Google Scholar 

  161. Witter MP (2007) The perforant path: projections from the entorhinal cortex to the dentate gyrus. Prog Brain Res 163:43–61

    PubMed  Google Scholar 

  162. Wu K, Leung LS (2001) Enhanced but fragile inhibition in the dentate gyrus in vivo in the kainic acid model of temporal lobe epilepsy: a study using current source density analysis. Neuroscience 104:379–396

    CAS  PubMed  Google Scholar 

  163. Ying SW, Futter M, Rosenblum K, Webber MJ, Hunt SP, Bliss TV, Bramham CR (2002) Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: requirement for ERK activation coupled to CREB and upregulation of Arc synthesis. J Neurosci 22:1532–1540

    CAS  PubMed  Google Scholar 

  164. Zhan RZ, Nadler JV (2009) Enhanced tonic GABA current in normotopic and hilar ectopic dentate granule cells after pilocarpine-induced status epilepticus. J Neurophysiol 102:670–681

    CAS  PubMed Central  PubMed  Google Scholar 

  165. Zhan RZ, Timofeeva O, Nadler JV (2010) High ratio of synaptic excitation to synaptic inhibition in hilar ectopic granule cells of pilocarpine-treated rats. J Neurophysiol 104:3293–3304

    PubMed Central  PubMed  Google Scholar 

  166. Zhang N, Wei W, Mody I, Houser CR (2007) Altered localization of GABA(A) receptor subunits on dentate granule cell dendrites influences tonic and phasic inhibition in a mouse model of epilepsy. J Neurosci 27:7520–7531

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This article is dedicated to Philip A. Schwartzkroin, a pioneer and leader in epilepsy research, esteemed mentor, and outstanding colleague.

Other Acknowledgements

Supported by R01 NS-081203, R21 MH-090606 and the New York State Office of Mental Health (HES) and R01 NS-038595, R01 NS-051710, R01-NS-050393 and grants from Citizens United for Research in Epilepsy, Department of Defense and the American Epilepsy Society (ABK).

Author information

Authors and Affiliations

  1. The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA

    Helen E. Scharfman

  2. Departments of Child & Adolescent Psychiatry, Physiology & Neuroscience, and Psychiatry, New York University Langone Medical Center, New York, NY, USA

    Helen E. Scharfman

  3. Departments of Pediatrics, Neurology and Pharmaceutical Sciences, University of Colorado School of Medicine, Aurora, CO, 80045, USA

    Amy R. Brooks-Kayal

  4. Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, 80045, USA

    Amy R. Brooks-Kayal

  5. Children’s Hospital Colorado, Aurora, CO, 80045, USA

    Amy R. Brooks-Kayal

Authors
  1. Helen E. Scharfman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amy R. Brooks-Kayal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Helen E. Scharfman .

Editor information

Editors and Affiliations

  1. Dept. of Child & Adoles. Psych., Phys. & Neurosc., and Psych., New York Univ. Langone Med. Ctr., Orangeburg, New York, USA

    Helen E. Scharfman

  2. Dept. of Comp. Med. and Neurol. & Neurol. Scs., Stanford University, Stanford, California, USA

    Paul S. Buckmaster

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Scharfman, H.E., Brooks-Kayal, A.R. (2014). Is Plasticity of GABAergic Mechanisms Relevant to Epileptogenesis?. In: Scharfman, H., Buckmaster, P. (eds) Issues in Clinical Epileptology: A View from the Bench. Advances in Experimental Medicine and Biology, vol 813. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-8914-1_11

Download citation

  • DOI: https://doi.org/10.1007/978-94-017-8914-1_11

  • Published:

  • Publisher Name: Springer, Dordrecht

  • Print ISBN: 978-94-017-8913-4

  • Online ISBN: 978-94-017-8914-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation