Role of Neurotransmitters in the Genesis of Epileptiform Discharges

  • K. Krnjević


The risk of excessive, runaway activity is probably inherent in the structure of cerebral cortex. Vast numbers of tightly packed, excitable cells—which can readily interact by releasing K+, by generating electrical fields and via direct or indirect excitatory synaptic paths—would inevitably undergo uncontrolled, paroxysmal depolarization and firing if indiscriminate excitation was not constantly opposed by very potent control mechanisms. The remarkable ability of the normal cortex to function for many years without any signs of major uncontrolled activity is irrefutable evidence of an astonishingly effective regulation of firing.


NMDA Receptor Hippocampal Neuron Excitatory Amino Acid Gaba Receptor Epileptiform Discharge 
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  1. Adams, P.R., and Brown, D.A., 1975, Actions of α-aminobutyric acid on sympathetic ganglion cells, J. Physiol. 250: 85–120.Google Scholar
  2. Aprison, M.H., and Werman, R., 1968, A combined neurochemical and neurophysiological approach to identification of central nervous system transmitters, in Neurosciences Research (S. Ehrenpreis and O.C. Solnitsky, eds.), Academic Press, New York, pp. 143–174.Google Scholar
  3. Ascher, P., and Nowak, L., 1988, Quisqualate-and kainate-activated channels in mouse central neurones in culture, J. Physiol. 399: 227–245.Google Scholar
  4. Ayala, G.F., Dichter, M., Gumnit, R.J., Matsumoto, H., and Spencer, W.A., 1973, Genesis of epileptic interictal spikes. New knowledge of cortical feedback systems suggests a neurophysiological explanation of brief paroxsyms, Brain Res. 52: 1–17.CrossRefGoogle Scholar
  5. Bakay, R.A.E., and Harris, A.B., 1981, Neurotransmitter, receptor and biochemical changes in monkey cortical epileptic foci, Brain Res. 206: 387–404.CrossRefGoogle Scholar
  6. Ben-Ari, Y., Krnjevic, K., and Reinhardt, W., 1979, Hippocampal seizures and failure of inhibition, Can. J. Physiol. Pharmacol. 57: 1462–1466.CrossRefGoogle Scholar
  7. Ben-Ari, Y., Krnjevic, K., Reiffenstein, R.J., and Reinhardt, W., 1981, Inhibitory conductance changes and action of γ-aminobutyrate in rat hippocampus, Neuroscience 6: 2445–2463.CrossRefGoogle Scholar
  8. Berridge, M.J., 1988, Inositol lipids and calcium signalling, Proc. R. Soc. Lond. (Biol.) 234: 359–378.CrossRefGoogle Scholar
  9. Biscoe, T.J., and Duchen, M.R., 1989, Electrophysiological responses of dissociated type I cells of the rabbit carotid body to cyanide, J. Physiol. 413: 447–468.Google Scholar
  10. Bormann, J., Hamill, O.P., and Sakmann, B., 1987, Mechanism of anion permeation through channels gated by glycine and gamma-aminobutyric acid in mouse cultured spinal neurones, J. Physiol. 385: 243–286.Google Scholar
  11. Bowery, N.G., Hill, D.R., Hudson, A.L., Doble, A., Middlemiss, D.N., Shaw, J., and Turnbull, M., 1980, (-)Baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor, Nature 283: 92–94.CrossRefGoogle Scholar
  12. Chesselet, M.-F., 1984, Presynaptic regulation of neurotransmitter release in the brain: Facts and hypothesis, Neuroscience 12: 347–375.CrossRefGoogle Scholar
  13. Choi, D.W., 1988, Calcium-mediated neurotoxicity relationship to specific channel types and role in ischemic damage, TINS 11: 465–469.Google Scholar
  14. Cook, N.S., 1988, The pharmacology of potassium channels and their therapeutic potential, TIPS 9: 21–28.Google Scholar
  15. Cull-Candy, S.G., and Usowicz, M.M., 1987, Multiple-conductance channels activated by excitatory amino acids in cerebellar neurons, Nature 325: 525–528.CrossRefGoogle Scholar
  16. Dalkara, T., 1986, Nipecotic acid, an uptake blocker, prevents fading of the α-aminobutyric acid effect, Brain Res. 366: 314–319.CrossRefGoogle Scholar
  17. Davidoff, R.A., Graham, L.T., Jr., Shank, R.P., Werman, R., and Aprison, M.H., 1967, Changes in amino acid concentrations associated with loss of spinal interneurons, J. Neurochem. 14: 1025–1031.CrossRefGoogle Scholar
  18. Dingledine, R., and Korn, S.J., 1985, α-Aminobuty-ric acid uptake and the termination of inhibitory synaptic potentials in the rat hippocampal slice, J. Physiol. 366: 387–409.Google Scholar
  19. Dreifuss, J.J., Kelly, J.S., and Krnjevic, K., 1969, Cortical inhibition and gamma-aminobutyric acid, Exp. Brain Res. 9: 137–154.CrossRefGoogle Scholar
  20. Dudek, F.E., Andrew, R.D., MacVicar, B.A., Snow, R.W., and Taylor, C.P., 1983, Recent evidence for and possible significance of gap junctions and electrotonic synapses in the mammalian brain, in Basic Mechanisms of Neuronal Hyper excitability, (H.H. Jasper and N.M. Van Gelder, eds.), Alan R. Liss Inc., New York, pp. 31–73.Google Scholar
  21. Dunwiddie, T.V., 1981, Age-related differences in the in vitro rat hippocampus, Dev. Neurosci. 4: 165–175.CrossRefGoogle Scholar
  22. Eccles, J.C., 1964, Presynaptic inhibition in the spinal cord, Progr. Brain Res. 12: 65–89.CrossRefGoogle Scholar
  23. Eccles, J.C., 1969, The Inhibitory Pathways of the Central Nervous System, Charles C. Thomas, Springfield, L.Google Scholar
  24. Eckert, R., and Chad, J.E., 1984, Inactivation of Ca channels, Progr. Biophys. Mol. Biol. 44: 215–267.CrossRefGoogle Scholar
  25. Finch, D.M., and Babb, T.L., 1977, Response decrement in a hippocampal basket cell, Brain Res. 130: 354–359.CrossRefGoogle Scholar
  26. Fujiwara, N., Higashi, H., Shimoji, K., and Yoshimura, M., 1987, Effects of hypoxia on rat hippocampal neurones in vitro, J. Physiol. 384: 131–151.Google Scholar
  27. Greene, R.W., and Haas, H.L., 1985, Adenosine actions on CA1 pyramidal neurones in rat hippocampal slices, J. Physiol. 366: 119–127.Google Scholar
  28. Grossman, R.G., 1968, Intracellular potentials of motor cortex neurons in cerebral ischemia, Elec-troencephalogr. Clin. Neurophysiol. 24: 291.CrossRefGoogle Scholar
  29. Hagiwara, S., 1983, Membrane potential-dependent ion channels in cell membrane. Phylogenetic and developmental approaches, Raven Press, New York.Google Scholar
  30. Hamill, O.P., Bormann, J., and Sakmann, B., 1983, Activation of multiple-conductance state chloride channels in spinal neurones by glycine and GABA, Nature 305: 805–808.CrossRefGoogle Scholar
  31. Heinemann, U., Lux, H.D., and Gutnick, M.J., 1977, Extracellular free calcium and potassium during paroxysmal activity in the cerebral cortex of the cat, Exp. Brain Res. 27: 237–243.CrossRefGoogle Scholar
  32. Hodgkin, A.L., and Huxley, A.F., 1952, The dual effect of membrane potential on sodium conductance in the giant axon of Loligo, J. Physiol. 116: 497–506.Google Scholar
  33. Hounsgaard, J., 1978, Inhibition produced by ion-tophoretically applied acetylcholine in area CA1 of thin hippocampal slices from the rat, Acta Physiol. Scand. 103: 110–111.CrossRefGoogle Scholar
  34. Houser, C.R., Vaughn, J.E., Hendry, S.H.C., Jones, E.G., and Peters, A., 1984, GABA neurons in the cerebral cortex, in Cerebral Cortex (E.G. Jones and A. Peters, eds.), Plenum Press, New York, pp. 63–89.Google Scholar
  35. Huguenard, J.R., and Alger, B.E., 1986, Whole-cell voltage-clamp study of the fading of GABA-activated currents in acutely dissociated hippocampal neurons, J. Neurophysiol. 56: 1–18.Google Scholar
  36. Inoue, M., Oomura, Y., Yakushiji, T., and Akaike, N., 1986, Intracellular calcium ions decrease the affinity of the GABA receptor, Nature 324: 156–158.CrossRefGoogle Scholar
  37. Ito, M., 1976, Roles of GABA neurons in integrated functions of the vertebrate CNS, in GABA in Nervous System Function (E. Roberts, T.N. Chase, and D.B. Tower, eds.), Raven Press, New York, pp. 427–448.Google Scholar
  38. Jahr, C.E., and Stevens, C.F., 1987, Glutamate activates multiple single channels conductances in hippocampal neurons, Nature 325: 522–525.CrossRefGoogle Scholar
  39. Johnson, J.W., and Ascher, P., 1987, Glycine potentiates the NMDA response in cultured mouse brain neurons, Nature 325: 529–531.CrossRefGoogle Scholar
  40. Johnston, D., and Brown, T.H., 1981, Giant synaptic potential hypothesis for epileptiform activity, Science 211: 294–297.CrossRefGoogle Scholar
  41. Kehl, S.J., and McLennan, H., 1985, An electrophysiological characterization of inhibitions and postsynaptic potentials in rat hippocampal CA3 neurones in vitro, Exp. Brain Res. 60: 299–308.Google Scholar
  42. Korn, S.J., and Dingledine, R., 1986, Inhibition of GABA uptake in the rat hippocampal slice, Brain Res. 368: 247–255.CrossRefGoogle Scholar
  43. Krnjević, K., 1976, Inhibitory action of GABA and GABA-mimetics on vertebrate neurons, in GABA in Nervous System Function (E. Roberts, T.N. Chase, and D.B. Tower, eds.), Raven Press, New York, pp. 269–281.Google Scholar
  44. Krnjevic, K., 1983, GABA-mediated inhibitory mechanisms in relation to epileptic discharges, in Basic Mechanisms of Neuronal Hyperexcitability (H.H. Jasper and N.M. van Gelder, eds.), Alan R. Liss Inc., New York, pp. 249–280.Google Scholar
  45. Krnjevic, K., Morris, M.E., and Reiffenstein, R.J., 1980, Changes in extracellular Ca2+ and K+ activity accompanying hippocampal discharges, Can. J. Physiol. Pharmacol. 58: 579–583.CrossRefGoogle Scholar
  46. Kudo, Y., and Ogura, A., 1986, Glutamate-induced increase in intracellular Ca2+ concentration in isolated hippocampal neurones, Br. J. Pharmacol. 89: 191–198.Google Scholar
  47. Kudo, Y., Ogura, A., and Iijima, T., 1988, Stimulation of muscarinic receptors in hippocampal neurons induces characteristic increase in cytoso-lic free Ca2+ concentration, Neurosci. Letts. 85: 345–350.CrossRefGoogle Scholar
  48. Kuffler, S.W., and Edwards, C., 1958, Mechanism of gamma aminobutyric acid (GABA) action and its relation to synaptic inhibition, J. Neurophysiol. 21: 589–610.Google Scholar
  49. Leblond, J.E., and Krnjevic, K., 1989, Hypoxic changes in hippocampal neurons, J. Neurophysiol. 62: 1–14.Google Scholar
  50. Levitan, E.S., Schofield, P.R., Burt, D.R., Rhee, L.M., Wisden, W., Köhler, M., Fujita, N., Rodriguez, H.F., Tephenson, A., Darlison, M.G., Barnard, E.A., and Seeburg, P.H., 1988, Structural and functional basis for GABA A receptor heterogeneity, Nature 335: 76–79.CrossRefGoogle Scholar
  51. Levy, R.A., 1980, Presynaptic control of input to the central nervous system, Can. J. Physiol. Pharmacol. 58: 751–766.CrossRefGoogle Scholar
  52. Lynch, G., and Baudry, M., 1984, The biochemistry of memory: A new and specific hypothesis, Science 224: 1057–1063.CrossRefGoogle Scholar
  53. MacDermott, A.B., and Dale, N., 1987, Receptors, ion channels and synaptic potentials underlying the integrative actions of excitatory amino acids, TINS 10: 280–284.Google Scholar
  54. MacDonald, J.F., and Wojtowicz, J.M., 1982, The effects of L-glutamate and its analogues upon the membrane conductance of central murine neurones in culture, Can. J. Physiol. Pharmacol. 60: 282–296.CrossRefGoogle Scholar
  55. Mayer, M.L., and Westbrook, G.L., 1987, The physiology of excitatory amino acids in the vertebrate central nervous system, Progr. Neurobiol. 28: 197–276.CrossRefGoogle Scholar
  56. McCarren, M., and Alger, B.E., 1985, Use-dependent depression of IPSPs in rat hippo-campal pyramidal cells in vitro, J. Neurophysiol. 53: 557–571.Google Scholar
  57. McCormick, D.A., and Pape, H.-C, 1988, Acetylcholine inhibits identified interneurons in the cat lateral geniculate nucleus, Nature 334: 246–248.CrossRefGoogle Scholar
  58. McLennan, H., 1983, Receptors for the excitatory amino acids in the mammalian central nervous system, Progr. Neurobiol. 20: 251–271.CrossRefGoogle Scholar
  59. Meldrum, B., 1986, Excitatory amino acid antagonists as novel anticonvulsants, in Excitatory Amino Acids and Epilepsy (R. Schwartz and Y. Ben-Ari, eds.), Plenum Press, New York, pp. 321–329.Google Scholar
  60. Mihara, S., North, R.A., and Surprenant, A., 1987, Somatostatin increases an inwardly rectifying potassium conductance in guinea-pig submucous plexus neurones, J. Physiol. 390: 335–355.Google Scholar
  61. Miledi, R., 1980, Intracellular calcium and desen-sitization of acetylcholine receptors, Proc. R. Soc. Lond. (Biol.) 209: 447–452.CrossRefGoogle Scholar
  62. Mody, I., Stanton, P.K., and Heinemann, U., 1988, Activation of N-methyl-D-aspartate receptors parallels changes in cellular and synaptic properties of dentate gyrus granule cells after kindling, J. Neurophysiol. 59: 1033–1054.Google Scholar
  63. Morris, M.E., Friedlich, J.J., and MacDonald, J.F., 1987, Intracellular calcium in mammalian brain cells: Fluorescence measurements with quin 2, Exp. Brain Res. 65: 520–526.CrossRefGoogle Scholar
  64. Nastuk, W., 1977, Ionophore-mediated calcium influx effects on the post-synaptic muscle fibre membrane, Nature 270: 441–443.CrossRefGoogle Scholar
  65. Nicoll, R.A., 1988, The coupling of neurotransmitter receptors to ion channels in the brain, Science 241: 545–551.CrossRefGoogle Scholar
  66. Nistri, A., and Constanti, A., 1979, Pharmacological characterization of different types of GABA and glutamate receptors in vertebrates and invertebrates, Progr. Neurobiol. 13: 117–235.CrossRefGoogle Scholar
  67. North, R.A., and Williams, J.T., 1985, On the potassium conductance increase by opioids in rat locus coeruleus neurones, J. Physiol. 364: 265–280.Google Scholar
  68. Nowak, L., Bregestovski, P., Ascher, P., Herbet, A., and Prochiantz, A., 1984, Magnesium gates glutamate-activated channels in mouse central neurones, Nature 307: 462–465.CrossRefGoogle Scholar
  69. Numann, R.E., and Wong, R.K.S., 1984, Voltage-clamp study of GABA response desensitization in single pyramidal cells dissociated from the hippocampus of adult guinea pigs, Neurosci. Letts. 47: 289–294.CrossRefGoogle Scholar
  70. Olsen, R.W., 1982, Drug interactions at the GABA receptor-ionophore complex, Ann. Rev. Pharmacol. Toxicol. 22: 247–277.CrossRefGoogle Scholar
  71. Ottersen, O.P., and Storm-Mathisen, J., 1987, Distribution of inhibitory amino acid neurons in the cerebellum with some observations on the spinal cord: An immunocytochemical study with an-tisera against fixed GABA, glycine, taurine, and β-alanine, J. Mind Behav. 8: 503–518.Google Scholar
  72. Polc, P., 1988, Electrophysiology of benzodiazepine receptor ligands: Multiple mechanisms and sites of action, Progr. Neurobiol. 31: 349–423.CrossRefGoogle Scholar
  73. Puil, E., 1981, S-glutamate: Its interactions with spinal neurons, Brain Res. Rev. 3: 229–322.CrossRefGoogle Scholar
  74. Racine, R., 1978, Kindling: The first decade. Neurosurgery 3: 234–252.CrossRefGoogle Scholar
  75. Ribak, C.E., 1987, GABAergic abnormalities occur in experimental models of focal and genetic epilepsy, J. Mind Behav. 8: 605[129]–618[142].Google Scholar
  76. Ribak, C.E., Harris, A.B., Vaughn, J.E., and Roberts, E., 1979, Inhibitory, GABAergic nerve terminals decrease at sites of focal epilepsy, Science 205: 211–214.CrossRefGoogle Scholar
  77. Ropert, N., and Krnjević, K., 1982, Pharmacological characteristics of facilitation of hippocampal population spikes by cholinomimetics, Neuroscience 7: 1963–1977.CrossRefGoogle Scholar
  78. Rovira, C., Ben-Ari, Y., and Cherubini, E., 1983, Dual cholinergic modulation of hippocampal somatic and dendritic field potentials by septo-hippocampal pathway, Exp. Brain Res. 49: 151–155.CrossRefGoogle Scholar
  79. Rovira, C., Ben-Ari, Y., and Cherubini, E., 1984, Somatic and dendritic actions of γ-aminobutyric acid agonists and uptake blockers in the hippocampus in vivo, Neuroscience 12: 543–555.CrossRefGoogle Scholar
  80. Segal, M., 1980, The action of serotonin in the rat hippocampal slice preparation, J. Physiol. 303: 423–439.Google Scholar
  81. Segal, M., 1983, Rat hippocampal neurons in culture: Responses to electrical and chemical stimuli, J. Neurophysiol. 50: 1249–1264.Google Scholar
  82. Starke, K., 1981, Presynaptic receptors, Ann. Rev. Pharmacol. Toxicol. 21: 7–30.CrossRefGoogle Scholar
  83. Stelzer, A., Slater, N.T., and ten Bruggencate, G., 1987, Activation of NMDA receptors blocks GABA-ergic inhibition on an in vitro model of epilepsy, Nature 326: 698–701.CrossRefGoogle Scholar
  84. Stelzer, A., Kay, A.R., and Wong, R.K.S., 1988, GABA-A-receptor function in hippocampal cells is maintained by phosphorylation factors, Science 241: 339–341.CrossRefGoogle Scholar
  85. Stephenson, F.A., 1988, Understanding the GABA A receptor: A chemically gated ion channel, Bio-chem.J. 249: 21–32.Google Scholar
  86. Taylor, C.P., and Dudek, F.E., 1982, Synchronous neural afterdischarges in rat hippocampal slices without active chemical synapses, Science 218: 810–812.CrossRefGoogle Scholar
  87. Thalmann, R.H., and Hershkowitz, N., 1985, Some factors that influence the decrement in the response to GABA during its continuous iontoph-retic application to hippocampal neurons, Brain Res. 342: 219–233.CrossRefGoogle Scholar
  88. Thomas, R.C., 1972, Electrogenic sodium pump in nerve and muscle cells, Physiol. Rev. 52: 563–594.Google Scholar
  89. Traub, R.D., Miles, R., and Wong, R.K.S., 1987, Models of synchronized hippocampal bursts in the presence of inhibition. I. Single population events, J. Neurophysiol. 58: 739–751.Google Scholar
  90. van Gelder, N.M., Siatitsas, I., Menini, C., and Gloor, P., 1983, Feline generalized penicillin epilepsy: Changes of glutamic acid and taurine parallel the progressive increase in excitability of the cortex, Epilepsia 24: 200–213.CrossRefGoogle Scholar
  91. van Harreveld, A., and Marmont, G., 1939, Time course of recovery of the spinal cord from asphyxia, J. Neurophysiol. 2: 101–111.Google Scholar
  92. Weiss, D.S., Barnes, E.M., and Hablitz, J.J., 1988, Whole-cell and single-channel recordings of GABA-gated currents in cultured chick cerebral neurons, J. Neurophysiol. 59: 495–513.Google Scholar
  93. Weiss, E.R., Kelleher, D.J., Woon, C.W., So-parkar, S., Osawa, S., Heasley, L.E., and Johnson, G.L., 1988, Receptor activation of G proteins, FASEB J. 2: 2841–2848.Google Scholar
  94. Williams, J.T., Henderson, G., and North, R.A. 1985, Characterization of α2-adrenoceptors which increase potassium conductance in rat locus coeruleus neurones, Neuroscience 14: 95–101.CrossRefGoogle Scholar
  95. Wong, R.K.S., and Watkins, D.J., 1982, Cellular factors influencing GABA response in hippocampal pyramidal cells, J. Neurophysiol. 48: 938–951.Google Scholar
  96. Yim, C.C., Krnjevic, K., and Dalkara, T., 1986, Ephaptically-generated potentials in CA1 neurons of rat’s hippocampus in situ, J. Neurophysiol. 56: 99–122.Google Scholar

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© Birkhäuser Boston, Inc. 1990

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  • K. Krnjević

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