Excitotoxicity on Cultured Cortical Neurons

  • D. W. Choi
Part of the Research and Perspectives in Neurosciences book series (NEUROSCIENCE)


This meeting is focused on two important properties of neurotransmitter glutamate. First, glutamate can regulate the long-term behavior of at least some of the excitatory synapses where it serves as neurotransmitter. This regulation provides a means for dynamic synaptic plasticity and may play a key role in normal functions such as memory and learning. Second, excess exposure to glutamate can destroy neurons, a process Olney (1986) called “excitotoxicity.” Excitotoxicity may contribute to pathogenesis of certain acute or chronic neurological diseases. While glutamate-mediated synaptic regulation and glutamate-mediated neuronal death occur in different settings, a theme of the present meeting is that the two processes may overlap substantially at the level of underlying mechanism.


NMDA Receptor Cortical Neuron Excitatory Amino Acid Domoic Acid Glutamate Toxicity 
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  1. Baimbridge KG, Kao J (1988) Calbindin D-28K protects against glutamate-induced neurotoxicity in rat CA1 pyramidal neuron cultures. Soc Neurosci Abstr 14:1264.Google Scholar
  2. Barbour B, Szatkowski M, Ingledew N, Attwell D (1989) Arachidonic acid induces a prolonged inhibition of glutamate uptake into glial cells. Nature 342:918–920.PubMedCrossRefGoogle Scholar
  3. Bazan NG (1989) Arachidonic acid in the modulation of excitable membrane function and at the onset of brain damage. Ann NY Acad Sci 1559:1–16.CrossRefGoogle Scholar
  4. Beal MF, Kowall NW, Ellison DW, Mazurek MF, Swartz KJ, Martin JB (1986) Replication of the neurochemical characteristics of Huntington’s disease by quinolinic acid. Nature 321:168–171.PubMedCrossRefGoogle Scholar
  5. Beal MF, Kowall NW, Swartz KJ, Ferrante RJ, Martin JB (1989) Differential sparing of somatostatin-neuropeptide Y and cholinergic neurons following striatal excitotoxin lesions. Synapse 3:38–47.PubMedCrossRefGoogle Scholar
  6. Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA (1990) Apparent hydroxyl radical production by peroxynitrite: Implications for endothelial injury from nitric oxide and Superoxide. Proc Natl Acad Sci USA 87:1620–1624.PubMedCrossRefGoogle Scholar
  7. Berdichevsky E, Riveros N, Sanchez-Armass S, Orrego F (1983) Kainate, N-methylaspartate and other excitatory amino acids increase calcium influx into rat brain cortex cells in vitro. Neurosci Lett 36:75–80.PubMedCrossRefGoogle Scholar
  8. Berridge MJ, Irvine RF (1989) Inositol phosphates and cell signalling. Nature 341:197–205.PubMedCrossRefGoogle Scholar
  9. Braughler JM, Pregenzer JF, Chase RL, Duncan LA, Jacobsen, EJ, McCall, JM (1987) Novel 21-amino steroids as potent inhibitors of iron-dependent lipid peroxidation. J Biol Chem 262:10438–10440.PubMedGoogle Scholar
  10. Chan PH, Fishman RA, Longar S, Chen S, Yu A (1985) Cellular and molecular effects of polyunsaturated fatty acids in brain ischemia and injury. Prog Brain Res 63:227–235.PubMedCrossRefGoogle Scholar
  11. Choi DW (1987) Ionic dependence of glutamate neurotoxicity in cortical cell culture. J Neurosci 7:369–379.PubMedGoogle Scholar
  12. Choi DW (1988a) Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage. Trends Neurosci 11:465–469.PubMedCrossRefGoogle Scholar
  13. Choi DW (1988b) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1:623–634.PubMedCrossRefGoogle Scholar
  14. Choi DW (1989) Non-NMDA receptor-mediated neuronal injury in Alzheimer’s disease? Neurobiol Aging 10:605–606.PubMedCrossRefGoogle Scholar
  15. Choi DW (1990a) Methods for antagonizing glutamate neurotoxicity. Cerebrovasc Brain Metab Rev 2:105–147.PubMedGoogle Scholar
  16. Choi DW (1990b) Cerebral hypoxia — some new approaches and unanswered questions. J Neurosci 10:2493–2501.PubMedGoogle Scholar
  17. Choi DW, Viseskul V, Amirthanayagam M, Monyer H (1989) Aspartate neurotoxicity on cultured cortical neurons. J Neurosci Res 23:116–121.PubMedCrossRefGoogle Scholar
  18. Cole AJ, Saffen DW, Baraban JM, Worley PF (1989) Rapid increase of an immediate early gene messenger RNA in hippocampal neurons by synaptic NMDA receptor activation. Nature 340:474–476.PubMedCrossRefGoogle Scholar
  19. Connor JA, Wadman WJ, Hockberger PE, Wong RK (1988) Sustained dendritic gradients of Ca2+ induced by excitatory amino acids in Cal hippocampal neurons. Science 240:649–653.PubMedCrossRefGoogle Scholar
  20. Coyle JT, Schwarcz R (1976) Lesion of striatal neurones with kainic acid provides a model for Huntington’s chorea. Nature 263:244–246.PubMedCrossRefGoogle Scholar
  21. Csermely P, Szarhel M, Resch K, Somogyi J (1988) Zinc increases the affinity of phorbol ester receptor in T lymphocytes. Biochem Biophys Res Comm 154:578–583.PubMedCrossRefGoogle Scholar
  22. Debonnel G, Beauchesne L, de-Montigny C (1989) Domoic acid, the alleged “mussel toxin,” might produce its neurotoxic effect through kainate receptor activation: an electrophysiological study in the dorsal hippocampus. Can J Physiol Pharmacol 67:29–33.PubMedCrossRefGoogle Scholar
  23. Diaz-Guerra MJ, Sanchez-Prieto J, Bosca L, Pocock J, Barrie A, Nicholls D (1988) Phorbol ester translocation of protein kinase C in guinea-pig synaptosomes and the potentiation of calcium-dependent glutamate release. Biochim Biophys Acta 970:157–165.PubMedCrossRefGoogle Scholar
  24. Dykens JA, Stern A, Trenkner E (1987) Mechanism of kainate toxicity to cerebellar neurons in vitro is analogous to reperfusion tissue injury. J Neurochem 49:1222–1228.PubMedCrossRefGoogle Scholar
  25. Ellren K, Lehmann A (1989) Calcium dependency of N-methyl-D-aspartate toxicity in slices from the immature rat hippocampus. Neurosci 132:371–379.CrossRefGoogle Scholar
  26. Favaron M, Manev H, Alho H, Bertolino M, Ferret B, Guidotti A, Costa E (1988) Gangliosides prevent glutamate and kainate neurotoxicity in primary neuronal cultures of neonatal rat cerebellum and cortex. Proc Natl Acad Sci USA 85:7351–7355.PubMedCrossRefGoogle Scholar
  27. Ferrante RJ, Kowall NW, Beal MF, Richardson EP, Bird ED, Martin JB (1985) Selective sparing of a class of striatal neurons in Huntington’s Disease. Science 230:561–563.PubMedCrossRefGoogle Scholar
  28. Finkbeiner S, Stevens CF (1988) Applications of quantitative measurements for assessing glutamate neurotoxicity. Proc Natl Acad Sci USA 85:4071–4074.PubMedCrossRefGoogle Scholar
  29. Frandsen A, Drejer J, Schousboe A (1989) Glutamate-induced 45Ca2+ uptake into immature cerebral cortex neurons shows a distinct pharmacological profile. J Neurochem 53:1959–1962.PubMedCrossRefGoogle Scholar
  30. Garthwaite J (1985) Cellular uptake disguises action of L-glutamate on N-methyl-D-aspartate receptors. With an appendix: diffusion of transported amino acids into brain slices. Br J Pharmacol 85:297–307.Google Scholar
  31. Garthwaite J, Charles SL, Chess-Williams R (1988) Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature 336:385–388.PubMedCrossRefGoogle Scholar
  32. Garthwaite G, Garthwaite J (1986) Neurotoxicity of excitatory amino acid receptor agonists in rat eerebellar slices: dependence on calcium concentration. Neursci Lett 66:193–198.CrossRefGoogle Scholar
  33. Garthwaite G, Garthwaite J (1989) Quisqualate neurotoxicity: a delayed, CNQX-sensitive process triggered by a CNQX-insensitive mechanism in young rat hippocampal slices. Neurosci Lett 99:113–118.PubMedCrossRefGoogle Scholar
  34. Giffard RG, Monyer H, Christine CW, Choi DW (1990) Acidosis reduces NMDA receptor activation, glutamate neurotoxicity, and oxygen-glucose deprivation neuronal injury in cortical cultures. Brain Res 506:339–342.PubMedCrossRefGoogle Scholar
  35. Hahn JS, Aizenman E, Lipton SA (1988) Central mammalian neurons normally resistant to glutamate toxicity are made sensitive by elevated extracellular Ca2+: toxicity is blocked by the N-methyl-D-aspartate antagonist MK-801. Proc Natl Acad Sci USA 85:6556–6560.PubMedCrossRefGoogle Scholar
  36. Harris EW, Stevens DR, Cotman CW (1987) Hippocampal cells primed with quisqualate are depolarized by AP4 and AP6, ligands for a putative glutamate uptake site. Brain Res 418:361–365.PubMedCrossRefGoogle Scholar
  37. Johnson JW, Ascher P (1987) Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325:529–531.PubMedCrossRefGoogle Scholar
  38. Kaczmarek LK (1987) The role of protein kinase C in the regulation of ion channels and neurotransmitter release. Trends Neurosci 10:30–34.CrossRefGoogle Scholar
  39. Kennedy MB (1989) Regulation of neuronal function by calcium. Trends Neurosci 12:417–420.PubMedCrossRefGoogle Scholar
  40. Kim JP, Choi DW (1987) Quinolinate neurotoxicity in cortical cell culture. Neuroscience 23:423–432.PubMedCrossRefGoogle Scholar
  41. Kim JP, Koh J, Choi DW (1987) L-Homocysteate is a potent neurotoxin on cultured cortical neurons. Brain Res 437:103–110.PubMedCrossRefGoogle Scholar
  42. Kimura H, Okamoto K, Sakai Y (1985) Modulatory effects of prostaglandin D2, E2 and F2 alpha on the postsynaptic actions of inhibitory and excitatory amino acids in eerebellar Purkinje cell dendrites in vitro. Brain Res 330:235–244.PubMedCrossRefGoogle Scholar
  43. Koh J, Choi DW (1988) Cultured striatal neurons containing NADPH-diaphorase or acetylcholinesterase are selectively resistant to injury by NMDA receptor agonists. Brain Res 446:374–378.PubMedCrossRefGoogle Scholar
  44. Koh J, Goldberg MP, Hartley DM, Choi DW (1990) Non-NMDA receptor-mediated neurotoxicity in cortical culture. J Neurosci 10:693–705.PubMedGoogle Scholar
  45. Koh J, Peters S, Choi DW (1986) Neurons containing NADPH-diaphorase are selectively resistant to quinolinate toxicity. Science 234:73–76.PubMedCrossRefGoogle Scholar
  46. Kurth MC, Weiss JH, Choi DW (1989) Relationship between glutamate-induced 45Ca influx and resultant neuronal injury in cultured cortical neurons. Neurology 39:217.Google Scholar
  47. Lipton SA, Kater SB (1989) Neurotransmitter regulation of neuronal outgrowth. plasticity and survival, trends Neurosci 12:265–270.Google Scholar
  48. Lynch G, Muller D, Seubert P, Larson J (1988) Long-term potentiation: persisting problems and recent results. Brain Res Bull 21:363–372.PubMedCrossRefGoogle Scholar
  49. Lysko PG, Cox JA, Vigano MA, Henneberry RC (1989) Excitatory amino acid neurotoxicity at the N-methyl-D-aspartate receptor in cultured neurons: pharmacological characterization. Brain Res 499:258–266.PubMedCrossRefGoogle Scholar
  50. MacDermott AB, Mayer ML, Westbrook GL, Smith SJ, Barker JL (1986) NMDA-receptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurones. Nature 321:519–522.PubMedCrossRefGoogle Scholar
  51. Malenka RC, Kauer JA, Perkel DJ, Nicoll RA (1989) The impact of postsynaptic calcium on synaptic transmission — its role in long-term potentiation. Trends Neurosci 12:444–450.PubMedCrossRefGoogle Scholar
  52. Malinow R, Schulman H, Tsien RW (1989) Inhibition of postsynaptic PKC or CaMKII blocks induction but not expression of LTP. Science 245:862–866.PubMedCrossRefGoogle Scholar
  53. Manev H, Favaron M, Guidotti A, Costa E (1989) Delayed increase of Ca2+ influx elicited by glutamate: role in neuronal death. Mol Pharmacol 36:106–112.PubMedGoogle Scholar
  54. Marcoux FW, Goodrich JE, Probert AW, Dominick MA (1983) Ketamine prevents glutamate-induced calcium influx and ischemia nerve cell injury. In: Domino EF, Kamenka J (eds) Sigma and Phenyclidine-Like Compounds as Molecular Probes in Biology. NPP Books, Ann Arbor, Michigan, pp 735–746.Google Scholar
  55. Mattson MP, Guthrie PB, Hayes BC, Kater SB (1990) Roles for mitotic history in the generation and degeneration of hippocampal neuroarchitecture. J Neurosci 9:1223–1232.Google Scholar
  56. McGeer EG, McGeer PL (1976) Duplication of biochemical changes of Huntington’s chorea by intrastriatal injections of glutamic and kainic acids. Nature 263:517–519.PubMedCrossRefGoogle Scholar
  57. Meldolesi J, Volpe P, Pozzan T (1988) The intracellular distribution of calcium. Trends Neurosci 11:449–452.PubMedCrossRefGoogle Scholar
  58. Meldrum B (1985) Possible therapeutic applications of antagonists of excitatory amino acid neurotransmitters. Clin Sci 68:113–122.PubMedGoogle Scholar
  59. Michaels RL, Rothman SM (1990) Glutamate neurotoxicity in vitro: Antagonist pharmacology and intracellular calcium concentrations. J Neurosci 10:283–292.PubMedGoogle Scholar
  60. Mody I, MacDonald JF, Baimbridge KG (1988) Release of intracellular calcium following activation of excitatory amino acid receptors in cultured hippocampal neurons. Soc Neurosci Abstr 14:94.Google Scholar
  61. Monyer H, Hartley DM, Ehsani H, Seeburg PH, Choi DW (1990) Muscimol attenuates slow excitatory amino acid-induced injury of cultured cortical neurons. Soc Neurosci Abst, in press.Google Scholar
  62. Morad M, Dichter M, Tang CM (1988) The NMDA activated current in hippocampal neurons is highly sensitive to [H+]. Soc Neurosci Abstr 14:791.Google Scholar
  63. Morgan JI, Curran T (1989) Stimulus-transcription coupling in neurons: role of cellular immediate-early genes. Trends Neurosci 12:459–462.PubMedCrossRefGoogle Scholar
  64. Murphy TH, Malouf AT, Sastre A, Schnaar RL, Coyle JT (1988) Calcium-dependent glutamate cytotoxicity in a neuronal cell line. Brain Res 444:325–332.PubMedCrossRefGoogle Scholar
  65. Murphy SN, Miller RJ (1989) Regulation of Ca++ influx into striatal neurons by kainic acid. J Pharmacol Exp Ther 249:184–193.PubMedGoogle Scholar
  66. Nachsen DA, Sanchez-Armass S, Weinstein Am (1986) The regulation of cytosolic calcium in rat brain synaptosomes by sodium-dependent calcium efflux. J Physiol 381:17–28.Google Scholar
  67. Nicoletti F, Wroblewski JT, Novelli A, Alho H, Guidotti A, Costa E (1986) The activation of inositol phospholipid metabolism as a signal-transducing system for excitatory amino acids in primary cultures of cerebellar granule cells. J Neurosci 6:1905–1911.PubMedGoogle Scholar
  68. Nishizuka Y (1986) Studies and perspectives of protein kinase C. Science 233:305–312.PubMedCrossRefGoogle Scholar
  69. Ogura A, Miyamoto M, Kudo Y (1988) Neuronal death in vitro: parallelism between survivability of hippocampal neurones and sustained elevation of cytosolic Ca2+ after exposure to glutamate receptor agonist. Exp Brain Res 73:447–458.PubMedCrossRefGoogle Scholar
  70. Olney JW (1986) Inciting excitotoxic cytocide among central neurons. Adv Exp Med Biol 203:631–645.PubMedGoogle Scholar
  71. Olney JW, Misra CH, Rhee V (1976) Brain and retinal damage from lathyrus excitotoxin, beta-N-oxalyl-L-alpha,beta-diaminopropionic acid. Nature 264:659–661.PubMedCrossRefGoogle Scholar
  72. Olney JW, Price MT, Samson L, Labruyere J (1986) The role of specific ions in glutamate neurotoxicity. Neurosci Lett 65:65–71.PubMedCrossRefGoogle Scholar
  73. Partridge LD, Swandulla D (1988) Calcium-activated non-specific cation channels. Trends Neurosci 11:69–72.PubMedCrossRefGoogle Scholar
  74. Pauwels PJ, Van-Assouw HP, Leysen JE, Janssen PA (1989) Ca2+-mediated neuronal death in rat brain neuronal cultures by veratridine: protection by flunarizine. Mol Pharmacol 36:525–531.PubMedGoogle Scholar
  75. Rondouin G, Drian MJ, Chicheportiche R, Kamenka JM, Privat A (1988) Non-competitive antagonists of N-methyl-D-aspartate receptors protect cortical and hippocampal cell cultures against glutamate neurotoxicity. Neurosci Lett 91:199–203.PubMedCrossRefGoogle Scholar
  76. Rosenberg PA, Aizenman E (1989) Hundred-fold increase in neuronal vulnerability to glutamate toxicity in astrocyte-poor cultures of rat cerebral cortex. Neurosci Lett 103:162–168.PubMedCrossRefGoogle Scholar
  77. Rothman, SM (1985) The neurotoxicity of excitatory amino acids is produced by passive chloride influx. J Neurosci 5:1483–14898.PubMedGoogle Scholar
  78. Rothman SM, Olney JW (1987) Excitotoxicity and the NMDA receptor. Trends Neurosci 10:299–302.CrossRefGoogle Scholar
  79. Rothman SM, Thurston JH, Hauhart RE (1987) Delayed neurotoxicity of excitatory amino acids in vitro. Neuroscience 22:471–480.PubMedCrossRefGoogle Scholar
  80. Siesjo BK, Rehncrona S, Smith D (1980) Neuronal cell damage in the brain: possible involvement of oxidative mechanisms. Acta Physiol Scand [Suppl] 492:121–128.Google Scholar
  81. Siman R, Noszek JC, Kegerise C (1989) Calpain I activation is specifically related to excitatory amino acid induction of hippocampal damage. J Neurosci 9:1579–1590.PubMedGoogle Scholar
  82. Sladeczek F, Pin JP, Recasens M, Bockaert J, Weiss S (1985) Glutamate stimulates inositol phosphate formation in striatal neurones. Nature 317:717–719.PubMedCrossRefGoogle Scholar
  83. Spencer PS, Ludolph A, Dwivedi MP, Roy DN, Hugon J, Schaumburg HH (1986) Lathyrism: evidence for role of the neuroexcitatory amino acid BOAA. Lancet 2:1066–1067.PubMedCrossRefGoogle Scholar
  84. Spencer PS, Nunn PB, Hugon J, Ludolph AC, Ross SM, Roy DN, Robertson RC (1987) Guam amyotrophic lateral sclerosis-Parkinsonism-dementia linked to a plant excitant neurotoxin. Science 237:517–522.PubMedCrossRefGoogle Scholar
  85. Stelzer A, Wong RK (1989) GABAA responses in hippocampal neurons are potentiated by glutamate. Nature 337:170–173.PubMedCrossRefGoogle Scholar
  86. Strong JA, Fox AP, Tsien RW, Kaczmarek LK (1987) Simulation of protein kinase C recruits covert calcium channels in Aplysia bag cell neurons. Nature 325:714–716.PubMedCrossRefGoogle Scholar
  87. Sugiyama K, Brunori A, Mayer ML (1989) Glial uptake of excitatory amino acids influences neuronal survival in cultures of mouse hippocampus. Neuroscience 132:779–791.CrossRefGoogle Scholar
  88. Sugiyama H, Ito I, Hirono C (1987) A new type of glutamate receptor linked to inositol phospholipid metabolism. Nature 325:531–533.PubMedCrossRefGoogle Scholar
  89. Szekely AM, Barbaccia ML, Alho H, Costa E (1989) In primary cultures of cerebellar granule cells the activation of N-methyl-D-aspartate-sensitive glutamate receptors induces c-fos mRNA expression. Mol Pharmacol 35:401–408.PubMedGoogle Scholar
  90. Traynelis SF, Cull-Candy SG (1990) Proton inhibition of N-methyl-D-aspartate receptors in cerebellar neurons. Nature 345:347–350.PubMedCrossRefGoogle Scholar
  91. Wahl P, Schousboe A, Honore T, Drejer J (1989) Glutamate-induced increase in intracellular Ca2+ in cerebral cortex neurons is transient in immature cells but permanent in mature cells. J Neurochem 53:1316–1319.PubMedCrossRefGoogle Scholar
  92. Weiss JH, Hartley DH, Koh J, Choi DW (1990a) Nifedipine attenuates slow excitatory amino acid neurotoxicity. Science 247:1474–1477.PubMedCrossRefGoogle Scholar
  93. Weiss JH, Koh J, Baimbridge KG, Choi DW (1990b) Cortical neurons containing somatostatin or parvalbumin-like immunoreactivity are atypically vulnerable to excitotoxic injury in vitro. Neurology 40:1288–1292.PubMedGoogle Scholar
  94. Weiss JH, Koh J, Choi DW (1989a) Neurotoxicity of beta-N-methylamino-L-alanine (BMAA) and beta-N-oxalylamino-L-alanine (BOAA) on cultured cortical neurons. Brain Res 497:64–71.PubMedCrossRefGoogle Scholar
  95. Weiss JH, Koh J, Christine CW, Choi DW (1989b) Zinc and LTP. [letter] Nature 338:212.PubMedCrossRefGoogle Scholar
  96. Yamamoto D (1988) Activation of protein kinase C promotes glutamate-mediated transmission at the neuromuscular junction of the mealworm. J Physiol 400:691–700.PubMedGoogle Scholar
  97. Yang X, Sachs F (1989) Block of stretch-activated ion channels in xenopus oocytes by gadolinium and calcium ions. Science 243:1068–1071.PubMedCrossRefGoogle Scholar
  98. Yu AC, Chan PH, Fishman RA (1987) Arachidonic acid inhibits uptake of glutamate and glutamine but not of GABA in cultured cerebellar granule cells. J Neurosci Res 17:424–427.PubMedCrossRefGoogle Scholar

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  • D. W. Choi

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