Induced and Acquired Epileptogenicity in Animal Models

  • Marco de Curtis
  • Giovanni Carriero
  • Gabriella Panuccio
  • Massimo Avoli
Reference work entry

This chapter discusses well-established animal models used to study the basic mechanisms of ictogenesis (i.e., models of seizures) and those developed to investigate the process of epileptogenesis (models of chronic epilepsy). For genetic models ( Genetic Animal Models of Epileptic Seizures) animal models have recently been extensively described and critically revised (Pitkänen 2006), and are further analyzed in other chapters of the Atlas.

Models of Seizures

This section includes the most common procedures utilized to generate seizures by acute electrical or pharmacological manipulations.

Drug-Induced Acute Models of Generalized Seizures

Besides rodent models of generalized seizures caused by systemic injection of convulsants, such as pentylenetrazole (PTZ; Ramzan and Levy 1985), most of the studies dealing with the fundamental mechanisms of generalized epilepsy stem from the intramuscular (i.m.) injection of large doses of penicillin in cats. This model, also known as feline...


Status Epilepticus Temporal Lobe Epilepsy Kainic Acid Febrile Seizure Clonic Seizure 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Ashwell K (1987) Altered morphology of dorsal lateral geniculate nucleus neurons in methylazoxymethanol acetate induced micrencephaly. Exp Brain Res 68:329–338CrossRefPubMedGoogle Scholar
  2. Avoli M, D'Antuono M, Louvel J, Kohling R, Biagini G, Pumain R, D'Arcangelo G, Tancredi V (2002) Network pharmachological mechanisms leading to epileptiform synchronization in the limbic system in vitro. Prog Neurobiol 68:167–207CrossRefPubMedGoogle Scholar
  3. Avoli M, Drapeau C, Louvel J, Pumain R, Olivier A, Villemure JG (1991) Epileptiform activity induced by low extracellular magnesium in the human cortex maintained in vitro. Ann Neurol 30:589–596CrossRefPubMedGoogle Scholar
  4. Avoli M, Rogawski MA, Avanzini G (2001) Generalized epileptic disorders: an update. Epilepsia 42:445–457CrossRefPubMedGoogle Scholar
  5. Bai J, Ramos RL, Ackman JB, Thomas AM, Lee RV, LoTurco JJ (2003) RNAi reveals doublecortin is required for radial migration in rat neocortex. Nat Neurosci 6:1277–1283CrossRefPubMedGoogle Scholar
  6. Baraban SC, Wenzel HJ, Hochman DW, Schwartzkroin PA (2000) Characterization of heterotopic cell clusters in the hippocampus of rats exposed to methylazoxymethanol in utero. Epilepsy Res 39(2):87–102CrossRefPubMedGoogle Scholar
  7. Ben-Ari Y, Tremblay E, Otterson OP (1980) Injection of kainic acid in the amygdaloid complex of the rat: an electroencephalographic, clinical and histological study in relation to the pathology of epilepsy. Neuroscience 5:15–52Google Scholar
  8. Benardete EA, Kriegstein AR (2002) Increased excitability and decreased sensitivity to GABA in an animal model of dysplastic cortex. Epilepsia 43:970–982CrossRefPubMedGoogle Scholar
  9. Browning RA, Nelson DK (1985) Variation in threshold and pattern of electroshock-induced seizures in rats depending on site of stimulation. Life Sci 37:2205–2211CrossRefPubMedGoogle Scholar
  10. Castro PA, Cooper EC, Lowenstein DH, Baraban SC (2001) Hippocampal heterotopia lack functional Kv4.2 potassium channels in the methylazoxymethanol model of cortical malformations and epilepsy. J Neurosci 21:6626–6634PubMedGoogle Scholar
  11. Cavalheiro EAN-MMGMLELJP (2006) The pilocarpine model of seizures. In: Pitkanen ASPAMSL (ed) Models of seizures and epilepsy. Elsevier Academic Press, Burlington, pp 433–446CrossRefGoogle Scholar
  12. Chevassus-Au-Louis N, Congar P, Represa A, Ben-Ari Y, Gaiarsa JL (1998) Neuronal migration disorders: heterotopic neocortical neurons in CA1 provide a bridge between the hippocampus and the neocortex. Proc Natl Acad Sci USA 95:10263–10268CrossRefPubMedGoogle Scholar
  13. Colacitti C, Sancini G, Franceschetti S, Cattabeni F, Avanzini G, Spreafico R, Di Luca M, Battaglia G (1998) Altered connections between neocortical and heterotopic areas in methylazoxymethanol-treated rat. Epilepsy Res 32(1–2):49–62CrossRefPubMedGoogle Scholar
  14. Colacitti C, Sancini G, DeBiasi S, Franceschetti S, Caputi A, Frassoni C, Cattabeni F, Avanzini G, Spreafico R, Di Luca M, Battaglia G (1999) Prenatal methylazoxymethanol treatment in rats produces brain abnormalities with morphological similarities to human developmental brain dysgeneses. J Neuropathol Exp Neurol 58:92–106CrossRefPubMedGoogle Scholar
  15. Collier PA, Ashwell KW (1993) Distribution of neuronal heterotopiae following prenatal exposure to methylazoxymethanol. Neurotoxicol Teratol 15:439–444CrossRefPubMedGoogle Scholar
  16. Contreras D, Steriade M (1995) Cellular basis of EEG slow rhythms: a study of dynamic corticothalamic relationships. J Neurosci 15:604–622PubMedGoogle Scholar
  17. Cossart R, Dinocourt C, Hirsch JC, Merchan-Perez A, De Felipe J, Ben-Ari Y, Esclapez M, Bernard C (2001) Dendritic but not somatic GABAergic inhibition is decreased in experimental epilepsy. Nat Neurosci 4:52–62CrossRefPubMedGoogle Scholar
  18. Cossart R, Esclapez M, Hirsch JC, Bernard C, Ben-Ari Y (1998) GluR5 kainate receptor activation in interneurons increases tonic inhibition of pyramidal cells. Nat Neurosci 1:470–478CrossRefPubMedGoogle Scholar
  19. D'Ambrosio R, Perucca E (2004) Epilepsy after head injury. Curr Opin Neurol 17:731–735CrossRefPubMedGoogle Scholar
  20. D'Ambrosio R, Fender JS, Fairbanks JP, Simon EA, Born DE, Doyle DL, Miller JW (2005) Progression from frontal-parietal to mesial-temporal epilepsy after fluid percussion injury in the rat. Brain 128(Pt 1):174–188PubMedGoogle Scholar
  21. Dickson CT, Alonso A (1997) Muscarinic induction of synchronous population activity in the entorhinal cortex. J Neurosci 17:6729–6744PubMedGoogle Scholar
  22. Dube CM, Brewster AL, Richichi C, Zha Q, Baram TZ (2007) Fever, febrile seizures and epilepsy. Trends Neurosci 30:490–496CrossRefPubMedGoogle Scholar
  23. Dudek EF CSPAWGHL (2006) Kainate-induced status epilepticus: a chronic model of acquired epilepsy. In: Pitkanen ASPAMSL (ed) Models of seizures and epilepsy. Elsevier Academic Press, Burlington, pp 415–432CrossRefGoogle Scholar
  24. Dvorak K, Feit J (1977) Migration of neuroblasts through partial necrosis of the cerebral cortex in newborn rats-contribution to the problems of morphological development and developmental period of cerebral microgyria. Histological and autoradiographical study. Acta Neuropathol 38:203–212CrossRefPubMedGoogle Scholar
  25. Fabene PF, Navarro MG, Martinello M, Rossi B, Merigo F, Ottoboni L, Bach S, Angiari S, Benati D, Chakir A, Zanetti L, Schio F, Osculati A, Marzola P, Nicolato E, Homeister JW, Xia L, Lowe JB, McEver RP, Osculati F, Sbarbati A, Butcher EC, Constantin G (2008) A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nat Med 14:1377–1383CrossRefPubMedGoogle Scholar
  26. Fisher RS, Alger BE (1984) Electrophysiological mechanisms of kainic acid-induced epileptiform activity in the rat hippocampal slice. J Neurosci 4:1312–1323PubMedGoogle Scholar
  27. Fueta Y, Avoli M (1993) Tetraethylammonium-induced epileptiform activity in young and adult rat hippocampus. Brain Res Dev Brain Res 72:51–58CrossRefPubMedGoogle Scholar
  28. Gardoni F, Pagliardini S, Setola V, Bassanini S, Cattabeni F, Battaglia G, Di Luca M (2003) The NMDA receptor complex is altered in an animal model of human cerebral heterotopia. J Neuropathol Exp Neurol 62:662–675PubMedGoogle Scholar
  29. Germano IM, Zhang YF, Sperber EF, Moshé SL (1996) Neuronal migration disorders increase susceptibility to hyperthermia-induced seizures in developing rats. Epilepsia 37:902–910CrossRefPubMedGoogle Scholar
  30. Giaretta D, Avoli M, Gloor P (1987) Intracellular recordings in pericruciate neurons during spike and wave discharges of feline generalized penicillin epilepsy. Brain Res 405(1):68–79CrossRefPubMedGoogle Scholar
  31. Gloor P, Fariello RG (1988) Generalized epilepsy: some of its cellular mechanisms differ from those of focal epilepsy. Trends Neurosci 11(2):63–68CrossRefPubMedGoogle Scholar
  32. Goddard GV, McIntyre DC, Leech CK (1969) A permanent change in brain function resulting from daily electrical stimulation. Exp Neurol 25:295–330CrossRefPubMedGoogle Scholar
  33. Hablitz JJ (1984) Picrotoxin-induced epileptiform activity in hippocampus: role of endogenous versus synaptic factors. J Neurophysiol 51:1011–1027PubMedGoogle Scholar
  34. Harrington EP, Moddel G, Najm IM, Baraban SC (2007) Altered glutamate receptor – transporter expression and spontaneous seizures in rats exposed to methylazoxymethanol in utero. Epilepsia 48:158–168CrossRefPubMedGoogle Scholar
  35. Holtzman D, Obana K, Olson J (1981) Hyperthermia-induced seizures in the rat pup: a model for febrile convulsions in children. Science 213:1034–1036CrossRefPubMedGoogle Scholar
  36. Honack D, Wahnschaffe U, Loscher W (1991) Kindling from stimulation of a highly sensitive locus in the posterior part of the piriform cortex. Comparison with amygdala kindling and effects of antiepileptic drugs. Brain Res 538:196–202CrossRefPubMedGoogle Scholar
  37. Jacobs KM, Gutnick MJ, Prince DA (1996) Hyperexcitability in a model of cortical maldevelopment. Cereb Cortex 6:514–523CrossRefPubMedGoogle Scholar
  38. Jensen FE, Applegate CD, Holtzman D, Belin TR, Burchfiel JL (1991) Epileptogenic effect of hypoxia in the immature rodent brain. Ann Neurol 29:629–637CrossRefPubMedGoogle Scholar
  39. Jensen FE, Holmes GL, Lombroso CT, Blume HK, Firkusny IR (1992) Age-dependent changes in long-term seizure susceptibility and behavior after hypoxia in rats. Epilepsia 33:971–980CrossRefPubMedGoogle Scholar
  40. Karhunen H, Jolkkonen J, Sivenius J, Pitkanen A (2005) Epileptogenesis after experimental focal cerebral ischemia. Neurochem Res 30:1529–1542CrossRefPubMedGoogle Scholar
  41. Kellinghaus C, Kunieda T, Ying Z, Pan A, Luders HO, Najm IM (2004) Severity of histopathologic abnormalities and in vivo epileptogenicity in the in utero radiation model of rats is dose dependent. Epilepsia 45:583–591CrossRefPubMedGoogle Scholar
  42. Kienzler F, Norwood BA, Sloviter RS (2009) Hippocampal injury, atrophy, synaptic reorganization, and epileptogenesis after perforant pathway stimulation-induced status epilepticus in the mouse. J Comp Neurol 515:181–196CrossRefPubMedGoogle Scholar
  43. Le Gal La Salle G, Feldblum S (1983) Role of the amygdala in development of hippocampal kindling in the rat. Exp Neurol 82:447–455CrossRefPubMedGoogle Scholar
  44. Lothman EW, Collins RC, Ferrendelli JA (1981) Kainic acid-induced limbic seizures: electrophysiologic studies. Neurology 31:806–812PubMedGoogle Scholar
  45. Luhmann HJ, Raabe K (1996) Characterization of neuronal migration disorders in neocortical structures: I. Expression of epileptiform activity in an animal model. Epilepsy Res 26:67–74CrossRefPubMedGoogle Scholar
  46. Luhmann HJ, Raabe K, Qu M, Zilles K (1998) Characterization of neuronal migration disorders in neocortical structures: extracellular in vitro recordings. Eur J Neurosci 10:3085–3094CrossRefPubMedGoogle Scholar
  47. Marchi N, Angelov L, Masaryk T, Fazio V, Granata T, Hernandez N, Hallene K, Diglaw T, Franic L, Najm I, Janigro D (2007) Seizure-promoting effect of blood-brain barrier disruption. Epilepsia 48:732–742CrossRefPubMedGoogle Scholar
  48. Mares P, Haugvicova R, Kubova H (2002) Unequal development of thresholds for various phenomena induced by cortical stimulation in rats. Epilepsy Res 49:35–43CrossRefPubMedGoogle Scholar
  49. Mellanby J, George G, Robinson A, Thompson P (1977) Epileptiform syndrome in rats produced by injecting tetanus toxin into the hippocampus. J Neurol Neurosurg Psychiatry 40:404–414CrossRefPubMedGoogle Scholar
  50. Morales DM, Marklund N, Lebold D, Thompson HJ, Pitkanen A, Maxwell WL, Longhi L, Laurer H, Maegele M, Neugebauer E, Graham DI, Stocchetti N, McIntosh TK (2005) Experimental models of traumatic brain injury: do we really need to build a better mousetrap? Neuroscience 136:971–989CrossRefPubMedGoogle Scholar
  51. Moshé SL (1981) The effects of age on the kindling phenomenon. Dev Psychobiol 14(1):75–81CrossRefPubMedGoogle Scholar
  52. Nagao T, Alonso A, Avoli M (1996) Epileptiform activity induced by pilocarpine in the rat hippocampal-entorhinal slice preparation. Neuroscience 72:399–408CrossRefPubMedGoogle Scholar
  53. Oby E, Janigro D (2006) The blood-brain barrier and epilepsy. Epilepsia 47:1761–1774CrossRefPubMedGoogle Scholar
  54. Pelletier MR, Carlen PL (1996) Repeated tetanic stimulation in piriform cortex in vitro: epileptogenesis and pharmachology. J Neurophysiol 76:4069–4079PubMedGoogle Scholar
  55. Pinel JP (1980) Alcohol withdrawal seizures: implications of kindling. Pharmacol Biochem Behav 13(Suppl 1):225–231PubMedGoogle Scholar
  56. Pitkänen A KINJMTK (2006) Posttraumatic epilepsy induced by lateral fluid-percussion brain injury in rats. In: Pitkanen ASPAMSL (ed) Models of seizures and epilepsy. Elsevier Academic Press, Burlington, pp 465–494CrossRefGoogle Scholar
  57. Pitkanen A, McIntosh TK (2006) Animal models of post-traumatic epilepsy. J Neurotrauma 23:241–261CrossRefPubMedGoogle Scholar
  58. Prince DA, Tseng GF (1993) Epileptogenesis in chronically injured cortex: in vitro studies. J Neurophysiol 69:1276–1291PubMedGoogle Scholar
  59. Rafiq A, DeLorenzo RJ, Coulter DA (1993) Generation and propagation of epileptiform discharges in a combined entorhinal cortex/hippocampal slice. J Neurophysiol 70:1962–1974PubMedGoogle Scholar
  60. Rafiq A, Zhang YF, DeLorenzo RJ, Coulter DA (1995) Long-duration self-sustained epileptiform activity in the hippocampal-parahippocampal slice: a model of status epilepticus. J Neurophysiol 74:2028–2042PubMedGoogle Scholar
  61. Ramzan IM, Levy G (1985) Kinetics of drug action in disease states. XIV. Effect of infusion rate on pentylenetetrazol concentrations in serum, brain and cerebrospinal fluid of rats at onset of convulsions. J Pharmacol Exp Ther 234:624–628PubMedGoogle Scholar
  62. Roper SN (1998) In utero irradiation of rats as a model of human cerebrocortical dysgenesis: a review. Epilepsy Res 32:63–74CrossRefPubMedGoogle Scholar
  63. Schuchmann S, Schmitz D, Rivera C, Vanhatalo S, Salmen B, Mackie K, Sipila ST, Voipio J, Kaila K (2006) Experimental febrile seizures are precipitated by a hyperthermia-induced respiratory alkalosis. Nat Med 12:817–823CrossRefPubMedGoogle Scholar
  64. Schwartzkroin PA, Prince DA (1977) Penicillin-induced epileptiform activity in the hippocampal in vitro prepatation. Ann Neurol 1:463–469CrossRefPubMedGoogle Scholar
  65. Schwartzkroin PA, Prince DA (1980) Changes in excitatory and inhibitory synaptic potentials leading to epileptogenic activity. Brain Res 183:61–76CrossRefPubMedGoogle Scholar
  66. Seiffert E, Dreier JP, Ivens S, Bechmann I, Tomkins O, Heinemann U, Friedman A (2004) Lasting blood-brain barrier disruption induces epileptic focus in the rat somatosensory cortex. J Neurosci 24:7829–7836CrossRefPubMedGoogle Scholar
  67. Singh SC (1977) Ectopic neurones in the hippocampus of the postnatal rat exposed to methylazoxymethanol during foetal development. Acta Neuropathol 40:111–116CrossRefPubMedGoogle Scholar
  68. Sloviter RS (2005) The neurobiology of temporal lobe epilepsy: too much information, not enough knowledge. C R Biol 328:143–153CrossRefPubMedGoogle Scholar
  69. Sperber EF, Veliskova J, Germano IM, Friedman LK, Moshe SL (1999) Age-dependent vulnerability to seizures. Adv Neurol 79:161–169PubMedGoogle Scholar
  70. Stasheff SF, Bragdon AC, Wilson WA (1985) Induction of epileptiform activity in hippocampal slices by trains of electrical stimuli. Brain Res 344:296–302CrossRefPubMedGoogle Scholar
  71. Swann JW, Brady RJ (1984) Penicillin-induced epileptogenesis in immature rat CA3 hippocampal pyramidal cells. Brain Res 314:243–254PubMedGoogle Scholar
  72. Tamaru M, Hirata Y, Nagayoshi M, Matsutani T (1988) Brain changes in rats induced by prenatal injection of methylazoxymethanol. Teratology 37:149–157CrossRefPubMedGoogle Scholar
  73. Toth Z, Yan XX, Haftoglou S, Ribak CE, Baram TZ (1998) Seizure-induced neuronal injury: vulnerability to febrile seizures in an immature rat model. J Neurosci 18:4285–4294PubMedGoogle Scholar
  74. Vernadakis A, Woodbury DM (1969) The developing animal as a model. Epilepsia 10:163–178CrossRefPubMedGoogle Scholar
  75. Williams PA, Dudek FE (2007) A chronic histopathological and electrophysiological analysis of a rodent hypoxic-ischemic brain injury model and its use as a model of epilepsy. Neuroscience 149:943–961CrossRefPubMedGoogle Scholar
  76. Williamson R, Wheal HV (1992) The contribution of AMPA and NMDA receptors to graded bursting activity in the hippocampal CA1 region in an acute in vitro model of epilepsy. Epilepsy Res 12:179–188CrossRefPubMedGoogle Scholar
  77. Zhu WJ, Roper SN (2000) Reduced inhibition in an animal model of cortical dysplasia. J Neurosci 20:8925–8931PubMedGoogle Scholar

Copyright information

© Springer-Verlag London Limited 2010

Authors and Affiliations

  • Marco de Curtis
    • 1
  • Giovanni Carriero
    • 1
  • Gabriella Panuccio
    • 2
  • Massimo Avoli
    • 2
    • 3
  1. 1.Unit of Experimental Neurophysiology and EpileptologyFondazione Istituto Neurologico Carlo BestaMilanItaly
  2. 2.Montreal Neurological Institute and Departments of Neurology & Neurosurgery and of PhysiologyMcGill UniversityMontrealCanada
  3. 3.Dipartimento di Medicina SperimentaleSapienza Università di RomaRomaItaly

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