On the Role of seizure Activity and Endogenous Excitatory Amino Acids in Mediating Seizure-Associated Hippocampal Damage

  • R. S. Sloviter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 203)


For many years, the brain damage associated with epilepsy was thought to be the result of anoxia believed to occur in brain regions susceptible to the effects of seizures (Meldrum and Corsellis, 1984). This was a reasonable supposition since anoxia causes neuron loss in some of the same brain regions affected in epilepsy (Meldrum and Corsellis, 1984). Two concurrent and related lines of research during the past fifteen years have significantly changed this view of epileptic brain damage. Meldrum and others have shown that although anoxia causes cell death, neither anoxia nor decreased blood flow occur in the affected brain regions during seizure activity (Meldrum and Corsellis, 1984). The second derives from the discovery by Olney (1978) that a number of endogenous excitatory amino acids are directly neurotoxic. This finding led to the ‘excitotoxic’ hypothesis which states that excitation and cell death are causally related and that, therefore, abnormal concentrations of endogenous excitatory amino acids could be responsible for the neuropathologie lesions seen in a number of neurologic disorders (Olney and de Gubareff, 1978). The subsequent discovery by Olney et al. (1974) of the neurotoxic and convulsant properties of the glutamate analog kainic acid served as a stimulus to research in experimental epilepsy in particular, since this compound rapidly and reliably produces a seizure state in normal animals that is associated with a pattern of brain damage (Nadler et al., 1978) similar to that seen in the brains of many chronic human epileptics (Meldrum and Corsellis, 1984). Our interest in this area of research began with the desire to understand how kainate caused hippocampal seizure activity and whether a direct neurotoxic effect of kainate or seizure activity per se causes hippocampal cell death. Olney et al. (1974) originally suggested that kainate produces excitation and cell death by an agonist action at glutamate receptors. Accordingly, the sensitivity of different hippocampal cell types to kainate (Nadler et al., 1978) was suggested to be due to differences in glutamate receptor density (Olney et al., 1979). On the basis of studies showing that transection of the mossy fiber pathway (Nadler and Cuthbertson, 1980) or pretreatment with diazepam (Ben-Ari et al., 1979) prevented kainateinduced hippocampal damage, it was alternately suggested that the hippocampal damage caused by kainate is due to seizure activity induced in the hippocampal granule cells by kainate (Ben-Ari et al., 1979; Nadler and Cuthbertson, 1980). According to this view, seizure activity in the mossy fiber pathway damages CA3 pyramidal cells by an unspecified mechanism that does not involve glutamate or glutamate receptors (Ben-Ari et al., 1979; Nadler and Cuthbertson, 1980). The results of studies by Olney et al., (1974), Nadler and colleagues (1980) and Crawford and Connor (1973) led us to form an hypothesis that accomodated both theories. Nadler et al. (1980) showed that among the hippocampal cells most sensitive to the neurotoxic effects of kainate were the cells of the dentate hilus. Some of these interneurons receive dense innervation from the granule cells (Amaral, 1978) and are believed to mediate recurrent inhibition in the granule cell layer (Andersen et al., 1966). We hypothesized at the time that if, as had been suggested by Crawford and Connor (1973), the granule cells use glutamate as a transmitter, then the inhibitory interneurons that receive dense innervation from the granule cells might possess the highest density of glutamate receptors. If, as suggested by Olney and colleagues (1974), kainate acts via glutamate receptors, then these inhibitory inter-neurons might be preferentially damaged by kainate. Since the loss of inhibition is associated with the onset of seizure activity (Roberts, 1980), we predicted that kainate injection might decrease inhibition first and cause granule cell seizure activity as a result. According to this scenario, granule cell seizure activity would release glutamate from the mossy fibers and cause damage to the CA3 pyramidal cells as a result. This hypothesis would explain how kainate initiates granule cell seizure activity and why transection of the mossy fiber pathway or diazepam protects the CA3 pyramidal cells. Since it was not known at the time if kainate affected inhibition or even if it caused hippocampal granule cell seizure activity, this seemed a worthwhile starting point. Our initial study with kainic acid, and experiments that were the logical extension of it, are reviewed in this chapter. They provide evidence that seizure activity per se causes neuronal damage and that the release of endogenous excitatory amino acids in high concentrations during seizures may mediate epileptic brain damage.


Granule Cell Seizure Activity Mossy Fiber Kainic Acid Granule Cell Layer 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Amaral, D.G., 1978, A Golgi study of cell types in the hilar region of the hippocampus in the rat, J. Comp. Neurol. 182:851.Google Scholar
  2. Andersen, P., Holmgvist, B., and Voorhoeve, P.E., 1966, Entorhinal activation of dentate granule cells, Acta Physiol. Scand. 66:448.Google Scholar
  3. Assaf, S.Y., and Chung, S.-H., 1984, Release of endogenous zinc from brain tissue during activity, Nature 308: 734.Google Scholar
  4. Ben-Ari, Y., Tremblay, E., Ottersen, 0.P., and Naquet, R., Evidence suggesting secondary epileptogenic lesions after kainic acid: pre-treatment with diazepam reduces distant but not local brain damage, Brain Res. 165:362.Google Scholar
  5. Ben-Ari, Y., 1985, Limbic seizure and brain damage produced by kainic acid: mechanisms and relevance to human temporal lobe epilepsy, Neuroscience 14: 375.Google Scholar
  6. Charton, G., Rovira, C., Ben-Ari, Y., and Leviel, V., 1985, Spontaneous and evoked release of zinc in the hippocampal mossy fiber zone of the rat in situ, Exp. Brain Res. 58:202.Google Scholar
  7. Crawford, I.L., and Connor, J.D., 1973, Localization and release of glutamic acid in relation to the hippocampal mossy fiber pathway, Nature 244: 442.Google Scholar
  8. Crawford, I.L., 1983, Zinc and the hippocampus, in: Neurobiology of the Trace Metals I.E. Dreosti and R.M. Smith, eds., Humana, Clifton, New Jersey, p. 163.Google Scholar
  9. Fisher, R.S., and Alger, B.E., 1984, Electrophysiological mechanisms of kainic acid-induced epileptiform activity in the rat hippocampal slice, J. Neurosci. 4:1312.Google Scholar
  10. Freeman, H., 1967, Crystal structure of metal-peptide complexes, Adv. Protein Chem., 22:257.Google Scholar
  11. Greenamyre, J.T., Olson, J.M.M., Penney, J.B., and Young, A.B., 1985, Autoradiographic characterization of N-methyl-D-aspartate-, quisqualateand kainate-sensitive glutamate binding sites, J. Pharmacol. Exp. Ther. 233:254.Google Scholar
  12. Haug, F.-M.S., 1967, Electron microscopical localization of the zinc in hippocampal mossy fiber synapses by a modified sulphide silver procedure, Histochemie 8: 355.Google Scholar
  13. Haug, F.-M.S., 1973, Heavy metals in the brain, Adv. Anat. Embryol. Cell Biol. 47:1.Google Scholar
  14. Howell, G.A., Welch, M.G., and Frederickson, C.J., 1984, Stimulation-induced uptake and release of zinc in hippocampal slices, Nature 308: 736.Google Scholar
  15. Kehl, S.J., McLennan, H., and Collingridge, G.L., 1984, Effects of folic and kainic acids on synaptic responses of hippocampal neurones, Neuroscience 11: 111.Google Scholar
  16. Lancaster, B., and Wheal, H.V., 1984, Chronic failure of inhibition of the CAS area of the hippocampus following kainic acid lesions of the CA3/4 area, Brain Res. 295: 317.Google Scholar
  17. Mangano, R.M., and Schwarcz, R., 1983, Chronic infusion of endogenous excitatory amino acids into rat striatum and hippocampus, Brain Res. Bull. 10:47.Google Scholar
  18. McBean G.J., and Roberts, P.J., 1984, Chronic infusion of L-glutamate causes neurotoxicity in rat striatum, Brain Res. 290: 372.Google Scholar
  19. Meldrum, B.S., and Corsellis, J.A.N., 1984, Epilepsy, in: Greenfield’s Neuropathology J.H. Adams, J.A.N. Corsellis and L.W. Duchen, eds., Wiley, New York, p. 921.Google Scholar
  20. Monaghan, D.T., and Cotman, C.W., 1982, The distribution of 3-H-kainic acid binding sites in rat CNS as determined by autoradiography, Brain Res., 252: 91.Google Scholar
  21. Monaghan, D.T., Holets, V.R., Toy, D.W., and Cotman, C.W., 1983, Anatomical distributions of four pharmacologically distinct 3-H-L-glutamate binding sites, Nature 306: 176.Google Scholar
  22. Nadler, J.V., Perry, B.W., and Cotman, C.W., 1978, Intraventricular kainic acid preferentially destroys hippocampal pyramidal cells, Nature 271: 676.Google Scholar
  23. Nadler, J.V., and Cuthbertson, G.J., 1980, Kainic acid neurotoxicity toward hippocampus: dependence on specific excitatory pathways, Brain Res. 195:47.Google Scholar
  24. Nadler, J.V., Evenson, D.A., and Cuthbertson, G.J., 1981, Comparative toxicity of kainic acid and other acidic amino acids toward rat hippocampal neurons, Neuroscience 6: 2505.Google Scholar
  25. Olney, J.W., Rhee, V., and Ho, O.L., 1974, Kainic acid: a powerful neuro-toxic analogue of glutamate, Brain Res. 77: 507.Google Scholar
  26. Olney, J.W., and de Gubareff, T., 1978, Glutamate neurotoxicity and Huntingtons chorea, Nature 271: 557.Google Scholar
  27. Olney, J.W., Fuller, T., and de Gubareff, T., 1979, Acute dendrotoxic changes in the hippocampus of kainate treated rats, Brain Res. 76:91. Olney, J.W., 1983, Excitotoxins, in: Excitotoxins K. Fuxe, P. Roberts, and R. Schwarcz, eds., Macmillan, London, p. 82.Google Scholar
  28. Olney, J.W., de Gubareff, T., and Sloviter, R.S., 1983, ‘Epileptic’ brain damage in rats induced by sustained electrical stimulation of the perforant path. II. Ultrastructural analysis of acute hippocampal pathology, Brain Res. Bull. 10:699.Google Scholar
  29. Roberts, F., 1980, Epilepsy and antiepileptic drugs: a speculative synthesis, in: Antiepileptic Drugs: Mechanisms of Action G.H. Glaser, J.K. Penry and D.M. Woodbury, eds., Raven Press, New York, p. 667.Google Scholar
  30. Schwarcz, R., Brush, G.S., Foster, A.C., and French, F.D., 1984, Seizure activity and lesions after intrahippocampal quinolinic acid injection, Exp. Neurol. 84:1.Google Scholar
  31. Sloviter, R.S., and Damiano, B.P., 1981a, On the relationship between kainic acid-induced epileptiform activity and hippocampal neuronal damage, Neuropharmacology 20: 1003.Google Scholar
  32. Sloviter, R.S., and Damiano, B.P., 1981b, Sustained electrical stimulation of the perforant path duplicates kainate-induced electrophysiological effects and hippocampal damage in rats, Neurosci. Lett. 24:279.Google Scholar
  33. Sloviter, R.S., 1983, ‘Epileptic’ brain damage in rats induced by sustained electrical stimulation of the perforant path. I. Acute electrophysiological and light microscopic studies, Brain Res. Bull. 10:675.Google Scholar
  34. Sloviter, R.S., 1985, A selective loss of hippocampal mossy fiber Timm stain accompanies granule cell seizure activity induced by perforant path stimulation, Brain Res. 330: 150.Google Scholar
  35. Sloviter, R.S., and Dempster, D.W., 1985, ‘Epileptic’ brain damage is replicated qualitatively in the rat hippocampus by central injection of glutamate or aspartate but not by GABA or acetylcholine, Brain Res. Bull. 15:39.Google Scholar
  36. Storm-Mathisen, J., and Iversen, L.L., 1979, Uptake of 3-H glutamic acid in excitatory nerve endings: light and electron microscopic observations in the hippocampal formation of the rat, Neuroscience 4: 1237.Google Scholar
  37. Storm-Mathisen, J., Leknes, A.K., Bore, A.T., Vaaland, J.L., Edminson, P., Haug, F.-M.S., and Ottersen, O.P., 1983, First visualization of glutamate and GABA in neurones by immunocytochemistry, Nature 301: 517.Google Scholar
  38. Werman, R.A., 1966, Criteria for identification of a central nervous system transmitter, Comp. Biochem. Physiol. 18:745.Google Scholar
  39. Westbrook, G.L., and Lothman, E.W., 1983, Cellular and synaptic basis of kainic acid-induced hippocampal epileptiform activity, Brain Res. 273:97.Google Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • R. S. Sloviter
    • 1
    • 2
  1. 1.Neurology Center, Helen Hayes HospitalNew York State Department of HealthWest HaverstrawUSA
  2. 2.Departments of Pharmacology and NeurologyColumbia UniversityNew YorkUSA

Personalised recommendations