Advertisement

Chronic focal epilepsy induced by intracerebral tetanus toxin

  • Jefferys J. G. R. 
  • Borck C. 
  • Mellanby J. 
Animal Models Relevant to Human Epilepsies

Abstract

A single, minute dose of tetanus toxin injected into mammalian cerebral cortex induces a chronic epileptic syndrome. Seizures lasting up to 3 minutes occur spontaneously and intermittently for several weeks to months. The cellular mechanisms of this model have been studied in detail using brain slicesin vitro. Initially the release of the inhibitory neurotransmitter, GABA, is blocked, but after 2–4 weeks, other mechanisms take over. Intrahippocampal tetanus toxin models human complex partial seizures (temporal lobe epilepsy). It results in consistent behavioural changes analogous with those seen clinically, in spite of the limited neuronal loss found in only 10–30% of rats. Treatment with carbamazepine ameliorates both the seizures and their behavioural consequences. Tetanus toxin provides a versatile and long-lasting model of focal epilepsies.

Key Words

tetanus toxin epileptic foci chronic model 

Sommario

La singola iniezione di una dose minima di tossina tetanica nella corteccia cerebrale dei mammiferi induce una sindrome epilettica cronica. Le crisi di durata fino a 3 minuti si manifestano spontaneamente in modo intermittente per parecchie settimane o mesi. I meccanismi cellulari di questo modello sono stati studiati in dettaglio in sezioni di tessuto cerebrale incubatein vitro. Inizialmente il rilascio del neurotrasmettitore inibitorio, GABA, è bloccato ma dopo 2–4 settimane subentrano attivi meccanismi. L'iniezione intraippocampale di tossina tetanica riproduce le crisi parziali complesse che si osservano nelle epilessie del lobo temporale. Essa determina modificazioni comportamentali analoghe a quelle osservate in clinica, malgrado il limitato danno neuronale, presente solo nel 10–30% dei ratti. Il trattamento con carbamazepina ha un effetto favorevole sia sulle crisi che sulle loro conseguenze comportamentali. La tossina tetanica permette di ottenere un modello versatile e persistente di epilessie focali.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. [1]
    Bagetta G., Corasaniti M.T., Nisticó G., Bowery N.G.:Behavioural and neuropathological effects produced by tetanus toxin injected into the hippocampus of rats. Neuropharmacol. 29:765–770 1990.Google Scholar
  2. [2]
    Brace H.M., Jefferys J.G.R., Mellanby J.:Long-term changes in hippocampal physiology and in learning ability of rats after intrahippocampal tetanus toxin. J. Physiol. (Lond.) 368:343–357, 1985.Google Scholar
  3. [3]
    Brener K., Chagnac-Amitai Y., Jefferys J.G.R., Gutnick M.J.:Chronic epileptic foci in neocortex: in vivo and in vitro effects of tetanus toxin. Eur. J. Neurosci. 3:47–54, 1991.PubMedGoogle Scholar
  4. [4]
    Chagnac-Amitai Y., Connors B.W.:Horizontal spread of synchronized activity in neocortex and its control by GABA-mediated inhibition. J. Neurophysiol. 61:747–758, 1989.PubMedGoogle Scholar
  5. [5]
    Darcey T.M., Williamson P.D.:Chronic/semichronic limbic epilepsy produced by microinjection of tetanus toxin in cat hippocampus. Epilepsia 33:402–419, 1992.PubMedGoogle Scholar
  6. [6]
    Empson R.M., Amitay Y., Jefferys J.G.R., Gutnick M.J.:Injection of tetanus toxin into the neocortex elicits persistent epileptiform activity but only transient impairment of GABA release. Neurosci. 57:235–239, 1993.Google Scholar
  7. [7]
    Empson R.M., Jefferys J.G.R.:Inhibitory synaptic function in primary and secondary chronic epileptic foci induced by intrahippocampal tetanus toxin in the rat. J. Physiol. (Lond.) 465:595–614, 1993.Google Scholar
  8. [8]
    Finnerty G.T., Jefferys J.G.R.:Spontaneous epileptiform activity in freely moving rats with epileptic foci induced by tetanus toxin. J. Physiol. (Lond.) 467:319P, 1993.Google Scholar
  9. [9]
    Hawkins C.A.:Studies on an animal model of temporal lobe epilepsy. D. Phil. thesis: Oxford University, 1985.Google Scholar
  10. [10]
    Hawkins C.A., Mellanby J., Brown J.:Antiepileptic and antiamnesic effect of carbamazepine in experimental limbic epilepsy. J. Neurol. Neurosurg. Psychiatry 48:459–468, 1985.PubMedGoogle Scholar
  11. [11]
    Hawkins C.A., Mellanby J.H.:Piracetam potentiates the antiepileptic action of carbamazepine in chronic experimental limbic epilepsy. Acta Neurol. Scand. 74 (suppl. 109): 117–121, 1986.Google Scholar
  12. [12]
    Hawkins C.A., Mellanby J.H.:Limbic epilepsy induced by tetanus toxin: a longitudinal electroencephalographic study. Epilepsia 28:431–444, 1987.PubMedGoogle Scholar
  13. [13]
    Jefferys J.G.R.:Chronic epileptic foci in vitro in hippocampal slices from rats with the tetanus toxin epileptic syndrome. J. Neurophysiol. 62:458–468, 1989.PubMedGoogle Scholar
  14. [14]
    Jefferys J.G.R., Empson R.M.:Development of chronic secondary epileptic foci following intrahippocampal injection of tetanus toxin. Exp. Physiol. 75:733–736, 1990.PubMedGoogle Scholar
  15. [15]
    Jefferys J.G.R., Evans B.J., Hughes S.A., Williams S.F.:Neuropathology of the chronic epileptic syndrome induced by intrahippocampal tetanus toxin in the rat: preservation of pyramidal cells and incidence of dark cells. Neuropathol. Appl. Neurobiol. 18:53–70, 1992.PubMedGoogle Scholar
  16. [16]
    Jefferys J.G.R., Williams S.F.:Physiological and behavioural consequences of seizures induced in the rat by intrahippocampal tetanus toxin. Brain 110:517–532, 1987.PubMedGoogle Scholar
  17. [17]
    Lee C., Hrachovy R., Smith K., Frost J.J., Swann J.:Seizures produced in neonatal rats by stereotaxic injection of tetanus toxin (TT): in vivo and in vitro models of seizures in early infancy. Soc. Neurosci. Abstr. 19:1870, 1993.Google Scholar
  18. [18]
    Louis E.D., Williamson P.D., Darcey T.M.:Chronic focal epilepsy induced by microinjection of tetanus toxin into the cat motor cortex. Electroencephalogr. Clin. Neurophysiol. 75:548–557, 1990.PubMedGoogle Scholar
  19. [19]
    Mellanby J.:Tetanus toxin as a tool for investigating the consequences of excessive neuronal excitation. In: Dasgupta, B.R. (ed.)Botulinum and tetanus neurotoxins, Plenum Press: New York, pp. 291–297, 1993.Google Scholar
  20. [20]
    Mellanby J., George G., Robinson A., Thompson P.:Epileptiform syndrome in rats produced by injecting tetanus toxin into the hippocampus. J. Neurol. Neurosurg. Psychiatry 40:404–414, 1977.PubMedGoogle Scholar
  21. [21]
    Mellanby J., Green J.:How does tetanus toxin act?. Neurosci. 6:281–300, 1981.Google Scholar
  22. [22]
    Mellanby J., Hawkins C., Mellanby H., Rawlins J.N.P., Impey M.E.:Tetanus toxin as a tool for studying epilepsy. J. Physiol. (Paris) 79:207–215, 1984.Google Scholar
  23. [23]
    Mellanby J., Strawbridge P., Collingridge G.I., George G., Rands G., Stroud C., Thompson:Behavioural correlates of an experimental hippocampal epileptiform syndrome in rats. J. Neurol. Neurosurg. Psychiatry 44:1084–1093, 1981.PubMedGoogle Scholar
  24. [24]
    Najlerahim A., Williams S.F., Pearson R.C.A., Jefferys J.G.R.:Increased expression of GAD mRNA during the chronic epileptic syndrome due to intrahippocampal tetanus toxin. Exp. Brain Res. 90:332–342, 1992.PubMedGoogle Scholar
  25. [25]
    Nicholls B., Shaw A., Mellanby J.H.:Effect of the NMDA receptor antagonist, D-2-amino-5-phosphonovaleric acid (D-APV) on tetanus toxin induced epileptiform syndrome. Neurosci. Lett. Suppl. 36:S25; 1989.Google Scholar
  26. [26]
    Roux E., Borrell A.:Tétanos cérébral et immunité contre le tétanos. Ann. Inst. Pasteur 4:225–239, 1898.Google Scholar
  27. [27]
    Schiavo G., Benfenati F., Poulain B., Rossetto O., Polverino de Laureto P., Dasgupta B.R., Montecucco C.:Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin. Nature 359:832–835, 1992.PubMedGoogle Scholar
  28. [28]
    Shaw J.A.G., Perry V.H., Mellanby J.:Tetanus toxin-induced seizures cause microglial activation in rat hippocampus. Neurosci. Lett. 120:66–69, 1990.PubMedGoogle Scholar
  29. [29]
    Shaw J.A.G., Perry V.H., Mellanby J.:MHC class II expression by microglia in tetanus toxininduced experimental epilepsy in the rat. Neuropathol. Appl. Neurobiol. 20:392–398, 1994.PubMedGoogle Scholar
  30. [30]
    Whittington M.A., Jefferys J.G.R.:Epileptic activity outlasts disinhibition after intrahippocampal tetanus toxin in the rat. J. Physiol. (Lond.) 481:593–604, 1994.Google Scholar

Copyright information

© Masson Italia Periodici S.r.l. 1995

Authors and Affiliations

  • Jefferys J. G. R. 
    • 1
    • 2
  • Borck C. 
    • 1
    • 2
  • Mellanby J. 
    • 1
    • 2
  1. 1.Department of Physiology and BiophysicsSt. Mary's Hospital Medical School, Imperial CollegeLondon
  2. 2.Department of Experimental PsychologyUniversity of OxfordOxfordUK

Personalised recommendations