Excitotoxicity and Neurodegenerative Disorders

  • Charles F. Zorumski
  • John W. Olney
Part of the Advances in Neuroprotection book series (AN, volume 22)


The excitatory amino acids (EAA) glutamate (Glu) and aspartate (Asp) are now recognized as key participants in a variety of physiologic and pathologic processes. On the one hand, these agents are likely to function as neurotransmitters at the majority of fast excitatory synapses in the vertebrate central nervous system (CNS), playing roles in normal synaptic transmission (Collingridge and Lester, 1989; Mayer and Westbrook, 1987a) and several forms of synaptic plasticity (Kuba and Kumamoto, 1990). Yet exposure of neurons to these agents clearly has toxic consequences, prompting hypotheses regarding the involvement of EAA in human neuro-degenerative syndromes (Olney, 1990). In this chapter we will review evidence linking EAA to specific neuropsychiatric syndromes.


Amyotrophic Lateral Sclerosis Excitatory Amino Acid NMDA Antagonist Domoic Acid Excitatory Amino Acid Receptor 
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  1. Albin RL, Young AB, Penney, JB (1989): The functional anatomy of basal ganglia disorders. Trends Neurosci 12: 366–375PubMedGoogle Scholar
  2. Arendash GW, Millard WJ, Dunn AJ, Meyer EM (1987): Long-term neuropathological and neurochemical effects of nucleus basalis lesions in the rat. Science 238: 952–956ADSPubMedGoogle Scholar
  3. Auer RN, Kalimo H, Olsson Y, Wieloch T (1985): The dentate gyrus in hypoglycemia. Pathology implicating excitotoxin-induced neuronal necrosis. Acta Neuropathol 67: 279–288PubMedGoogle Scholar
  4. Bartus RT, Dean RC, Beer B, Lippa AS (1982): Cholinergic hypothesis of geriatric memory dysfunction. Science 217: 408–417ADSPubMedGoogle Scholar
  5. Beal MF, Kowall NW, Ellison DW, Mazurek MF, Swartz KJ (1986): Replication of the neurochemical characteristics of Huntington’s disease by quinolinic acid. Nature 321: 168–171ADSPubMedGoogle Scholar
  6. Bear MF, Cooper LN, Ebner FF (1987): A physiological basis for a theory of synapse modification. Science 237: 42–48ADSPubMedGoogle Scholar
  7. Benveniste H, Drejer J, Schousboe A, Diemer NM (1984): Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem 43: 1369–1374CrossRefGoogle Scholar
  8. Berridge MJ (1987): Inositol trisphosphate and diacyglycerol: Two interacting second messengers. Annu Rev Biochem 56: 159–193PubMedGoogle Scholar
  9. Boulter J, Hollmann M, O’Shea-Greenfield A, Hartley M, Deneris E, Maron C, Heinemann S (1990): Molecular cloning and functional expression of glutamate receptor subunit genes. Science 249: 1033–1037ADSPubMedGoogle Scholar
  10. Bridges RJ, Stevens DR, Kahle JS, Nunn PB, Kadri M, Cotman CW (1989): Structure-function studies on N-oxalyl-diamino-dicarboxylic acids and excitatory amino acid receptors: Evidence that 3-L-ODAP is a selective non-NMDA agonist. J Neurosci 9: 2073–2079PubMedGoogle Scholar
  11. Choi DW (1987): Ionic dependence of glutamate neurotoxicity. J Neurosci 7: 369–379Google Scholar
  12. Choi DW (1988): Glutamate neurotoxicity and diseases of the nervous system. Neuron 1: 623–634CrossRefGoogle Scholar
  13. Choi DW (1990): Cerebral hypoxia: Some new approaches and unanswered questions. J Neurosci 10:2493–2501 Google Scholar
  14. Choi DW, Maulucci-Gedde M, Kriegstein AR (1987): Glutamate neurotoxicity in cortical cell culture. J Neurosci 7: 357–368PubMedGoogle Scholar
  15. Clifford DB, Olney JW, Benz AM, Fuller TA, Zorumski CF (1990): Ketamine, phencyclidine and MK-801 protect against kainic acid induced seizure-related brain damage. Epilepsia 31: 382–390PubMedGoogle Scholar
  16. Clifford DB, Zorumski CF, Olney JW (1989): Ketamine and MK-801 prevent degeneration of thalamic neurons induced by focal cortical seizures. Exp Neurol 105: 272–279PubMedGoogle Scholar
  17. Collingridge GL, Lester RAJ (1989): Excitatory amino acid receptors in the vertebrate central nervous system. Pharm Rev 40: 143–210Google Scholar
  18. Collins RC, Olney JW (1982): Focal cortical seizures cause distant thalamic lesions. Science 218: 177–179ADSPubMedGoogle Scholar
  19. Copani A, Canonico PL, Nicoletti F (1990): 13-N-Methylamino-L-alanine (L-BMAA) is a potent agonist of metabolotropic glutamate receptors. Eur J Pharmacol 181: 327–328PubMedGoogle Scholar
  20. Cotman CW, Flatman JA, Ganong AH, Perkins MN (1986): Effects of excitatory amino acid antagonists on evoked and spontaneous excitatory potentials in guinea pig hippocampus. J Physiol (Lond) 378: 403–415Google Scholar
  21. Coyle JT, McGeer EF, McGeer PL, Schwarcz R (1978): Neostriatal injections: A model for Huntington’s chorea. In: Kainic Acid as a Tool in Neurobiology, McGeer E, Olney JW, McGeer P, eds. New York: Raven Press, pp 139–159Google Scholar
  22. Coyle JT, Price DL, DeLong MA (1983): Alzheimer’s disease: A disorder of cortical cholinergic innervation. Science 219: 1184–1190ADSPubMedGoogle Scholar
  23. Curtis DR, Watkins JC (1960): The excitation and depression of spinal neurons by structurally related amino acids. J Neurochem 6: 117–141PubMedGoogle Scholar
  24. DeBoni U, McLachlan DRC (1985): Controlled induction of paired helical filaments of the Alzheimer type in cultured human neurons by glutamate and aspartate. J Neurol Sci 68: 105–118Google Scholar
  25. Faden AI, Demediuk P, Panter S, Vink R (1989): The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 244: 798–800ADSPubMedGoogle Scholar
  26. Foster AC, Fagg GE (1984): Acidic amino acid binding sites in mammalian neuronal membranes: Their characteristics and relationship to synaptic receptors. Brain Res Rev 7: 103–164Google Scholar
  27. Gay VL, Plant TM (1987): N-Methyl-D-aspartate elicits hypothalamic gonadotropinreleasing hormone release in prepubertal male rhesus monkeys (Macaca mulatta). Endocrinology 120: 2289–2296PubMedGoogle Scholar
  28. Heafield MT, Fearn S, Steventon GB, Waring RH, Williams AD, Sturman SG (1990): Plasma cysteine and sulfate levels in patients with motor neurone, Parkinson’s and Alzheimer’s disease. Neurosci Lett 110: 216–220PubMedGoogle Scholar
  29. Honoré T, Davies SN, Drejer J, Fletcher EJ, Jacobsen P, Lodge D, Nielsen FE (1988): Quinoxalinediones: Potent competitive non-NMDA glutamate receptor antagonists. Science 241: 701–703ADSPubMedGoogle Scholar
  30. Ikonomidou C, Price MT, Mosinger JL, Friedrich G, Labruyere J, Salles KS, Olney JW (1989): Hypobaric-ischemic conditions produce glutamate-like cytopathology in infant rat brain. J Neurosci 9: 1693–1700PubMedGoogle Scholar
  31. Johnson JW, Ascher P (1987): Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325: 529–531ADSPubMedGoogle Scholar
  32. Katayama Y, Cheung MK, Gorman L, Tamura T, Becker DP (1988): Increase in extracellular glutamate and associated massive ionic fluxes following concussive brain injury. Neurosci Abstr 14: 1154Google Scholar
  33. 340.
    Charles F. Zorumski and John W. OlneyGoogle Scholar
  34. Keinanen K, Wisden W, Sommer B, Werner P, Herb A, Verdoorn TA, Sakmann B, Seeburg PH (1990): A family of AMPA-selective glutamate receptors. Science 249: 556–560ADSPubMedGoogle Scholar
  35. Koh JY, Goldberg MP, Hartley DM, Choi DW (1990): Non-NMDA receptor-mediated neurotoxicity in cortical culture. J Neurosci 10: 693–705PubMedGoogle Scholar
  36. Kuba K, Kumamoto E (1990): Long-term potentiation in vertebrate synapses: A variety of cascades with common subprocesses. Prog Neurobiol 34: 197–269PubMedGoogle Scholar
  37. Lothman EW, Collins RC (1981): Kainic acid induced limbic seizures: Metabolic, behavioral, electroencephalographic and neuropathological correlates. Brain Res 218: 299–318PubMedGoogle Scholar
  38. Lucas DR, Newhouse JP (1957): The toxic effect of sodium L-glutamate on the inner layers of the retina. AMA Arch Ophthalmol 58: 193–201PubMedGoogle Scholar
  39. Maragos WF, Greenamyre JT, Penney JB, Young AB (1987): Glutamate dysfunc-tion in Alzheimer’s disease: An hypothesis. Trends Neurosci 10: 65–68Google Scholar
  40. Mattson MP, Dou P, Kater SB (1988): Outgrowth regulating actions of glutamate in isolated hippocampal pyramidal neurons. J Neurosci 8: 2087–2100PubMedGoogle Scholar
  41. Mayer ML, Westbrook GL (1984): Mixed agonist action on excitatory amino acids on mouse spinal cord neurons under voltage-clamp. J Physiol (Lond) 354: 29–53Google Scholar
  42. Mayer ML, Westbrook GL, Guthrie PB (1984): Voltage-dependent block by Mg’ of NMDA responses in spinal cord neurons. Nature 309: 261–263ADSPubMedGoogle Scholar
  43. Mayer ML, Westbrook GL (1987a). The physiology of excitatory amino acids in the vertebrate central nervous system. Prog Neurobiol 28: 197–276PubMedGoogle Scholar
  44. Mayer ML, Westbrook GL (1987b). Permeation and block of N-methyl-D-aspartic acid receptor channels by divalent cations in mouse cultured central neurones. J Physiol (Lond) 394: 501–527Google Scholar
  45. Miller R, Slaughter M (1986): Excitatory amino acid receptors of the retina: Diversity of subtypes and conductance mechanisms. Trends Neurosci 9: 211–218Google Scholar
  46. Monaghan DT, Bridges RJ, Cotman CW (1989): The excitatory amino acid receptors: Their classes, pharmacology and distinct properties in the function of the central nervous system. Annu Rev Pharmacol Toxico! 29: 365–402Google Scholar
  47. Mudd SH, Irreverre F, Laster L (1967): Sulfite oxidase deficiency in man: Demonstration of the enzyme defect. Science 156: 1599–1602ADSPubMedGoogle Scholar
  48. Nunn PB, Davis AJ, O’Brien P (1991): On carbamate formation and the neurotoxicity of L-a-amino acids. Science 251: 1619–1620ADSPubMedGoogle Scholar
  49. Olney JW (1969a): Glutamate-induced retinal degeneration in neonatal mice: Electron microscopy of the acutely evolving lesion. J Neuropathol Exp Neurol 28: 455–474PubMedGoogle Scholar
  50. Olney JW (1969b): Brain lesions, obesity and other disturbances in mice treated with monosodium glutamate. Science 164: 719–721ADSPubMedGoogle Scholar
  51. Olney JW (1971): Glutamate-induced neuronal necrosis in the infant mouse hypothalamus: An electron microscopic study. J Neuropathol Exp Neurol 30: 75–90Google Scholar
  52. Olney JW (1979): Excitotoxic amino acids and Huntington’s disease. Advan Neurol (Huntington’s Disease) 23: 609–624Google Scholar
  53. Olney JW (1990): Excitotoxic amino acids and neuropsychiatric disorders. Annu Rev Pharmacol Toxicol 30: 47–71PubMedGoogle Scholar
  54. Olney JW, DeGubareff T, Sloviter RS (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: 699–712PubMedGoogle Scholar
  55. Olney JW, Ho OL, Rhee V (1971): Cytotoxic effects of acidic and sulphur-containing amino acids on the infant mouse central nervous system. Exp Brain Res 14: 61–76Google Scholar
  56. Olney JW, Ho OL, Rhee V, Schainker B (1972a): Cysteine induced brain damage in infant and fetal rodents. Brain Res 45: 309–313PubMedGoogle Scholar
  57. Olney JW, Labruyere J, deGubareff T (1980): Brain damage in mice from voluntary ingestion of glutamate and aspartate. Neurobehav Toxico! 2: 135–129Google Scholar
  58. Olney JW, Labruyere J, Price MT (1989): Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 244: 1360–1362ADSPubMedGoogle Scholar
  59. Olney JW, Misra CH, deGubareff T (1975): Cysteine-S-sulfate: A brain damaging metabolite in sulfite oxidase deficiency. J Neuropathol Exp Neurol 34: 167–176PubMedGoogle Scholar
  60. Olney JW, Misra CH, Rhee V (1976): Brain and retinal damage from the lathyrus excitotoxin, (3-N-oxalyl-L-a,ß-diaminopropionic acid (ODAP). Nature 264: 659–661ADSPubMedGoogle Scholar
  61. Olney JW, Price MT (1980): Neuroendocrine interactions of excitatory and inhibitory amino acids. Brain Res Bull 5 (Suppl 2): 361–368Google Scholar
  62. Olney JW, Price MT, Samson L, Labruyere J (1986): The role of specific ions in glutamate neurotoxicity. Neurosci Lett 65: 65–71PubMedGoogle Scholar
  63. Olney JW, Sharpe LG, Feigin RD (1972b): Glutamate induced brain damage in infant primates. J Neuropathol Exp Neurol 31: 464–488PubMedGoogle Scholar
  64. Olney JW, Zorumski C, Price MT, Labruyere J (1990a): L-Cysteine, a bicarbonate sensitive endogenous excitotoxin. Science 248: 596–599ADSPubMedGoogle Scholar
  65. Olney JW, Zorumski CF, Stewart GR, Price MT, Wang G, Labruyere J (1990b): Excitotoxicity of L-DOPA and 6-OH-DOPA: Implications for Parkinson’s and Huntington’s diseases. Exp Neurol 108: 269–272PubMedGoogle Scholar
  66. Perl TM, Bedard L, Kosatsky T, Hockin JC, Todd ECD, Remis RS (1990): An outbreak of toxic encephalopathy caused by eating mussels contaminated with domoic acid. New Engl JMed 322: 1775–1780Google Scholar
  67. Plaitakis A, Berl S, Yahr M (1984): Neurological disorders associated with deficiency of glutamate dehydrogenase. Ann Neuro! 15: 144–153Google Scholar
  68. Plaitakis A, Caroscio JT (1987): Abnormal glutamate metabolism in amyotrophic lateral sclerosis. Ann Neuro! 22: 575–579Google Scholar
  69. Plant TM, Gay VL, Marshall GR, Arslan M (1989): Puberty in monkeys is triggered by chemical stimulation of the hypothalamus. Proc Natl Acad Sci USA 86: 2506–2510ADSPubMedGoogle Scholar
  70. Price MT, Olney JW, Anglim M, Buchsbaum S (1979): Reversible action of N-methyl aspartate on gonadotropin neuroregulation. Brain Res 176: 165–168PubMedGoogle Scholar
  71. Procter AW, Palmer AM, Frances PT, Lowe SL, Neary D, Murphy E, Doshi R, Bowen DM (1988): Evidence of glutamatergic denervation and possible abnormal metabolism in Alzheimer’s disease. J Neurochem 50: 790–802PubMedGoogle Scholar
  72. Reynolds GP, Pearson SJ, Halket J, Sandler M (1988): Brain quinolinic acid in Huntington’s disease. J Neurochem 50: 1959–1960PubMedGoogle Scholar
  73. Ross SM, Roy DN, Spencer PS (1989): ß-N-Oxalylamino-L-alanine action on glutamate receptors. J Neurochem 53: 710–715PubMedGoogle Scholar
  74. Rothman SM (1984): Synaptic release of excitatory amino acid neurotransmitter mediates anoxic neuronal death. J Neurosci 4: 1884–1891PubMedGoogle Scholar
  75. Rothman SM (1985): The neurotoxicity of excitatory amino acids is by passive chloride influx. J Neurosci 5: 1483–1489PubMedGoogle Scholar
  76. Rothstein JD, Tsai G, Kund RW, Clawson L, Cornblath DR, Drachman DB, Pestronk A, Stauch BL, Coyle JT (1990): Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. Ann Neuro! 28: 18–25Google Scholar
  77. Schwarcz R, Kohler C (1983): Differential vulnerability of central neurons of the rat to quinolinic acid. Neurosci Lett 38: 85–90PubMedGoogle Scholar
  78. Simon RP, Swan JH, Griffiths T, Meldrum BS (1984): Blockade of N-methyl-Daspartate receptors may protect against ischemic damage in the brain. Science 226: 850–852ADSPubMedGoogle Scholar
  79. Slevin JT, Collins JF, Coyle JT (1983): Analogue interactions with the brain receptor labeled by [3H]kainic acid. Brain Res 265: 169–172PubMedGoogle Scholar
  80. Sofroniew MV, Pearson RCA (1985): Degeneration of cholinergic neurons in the basal nucleus following kainic or N-methyl-D-aspartic acid application to the cerebral cortex in the rat. Brain Res 339: 186–190PubMedGoogle Scholar
  81. Sommer B, Keinanen K, Verdoorn TA, Wisden W, Burnashev N, Herb A, Kohler M, Takagi T, Sakmann B, Seeburg PH (1990): Flip and flop. A cell specific functional switch in glutamate operated channels of the CNS. Science 249: 1580–1585ADSPubMedGoogle Scholar
  82. Spencer PS, Allen RG, Kisby GE, Ludolph AC (1990): Excitotoxic disorders. Science 248: 144ADSPubMedGoogle Scholar
  83. Spencer PS, Ludolph A, Dwivedi MP, Roy DN, Hugon J, Schaumbure HH (1986): Lathyrism: Evidence for a role of the neuroexcitatory amino acid BOAA. Lancet 2: 1066–1067PubMedGoogle 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: 517–522ADSPubMedGoogle Scholar
  85. Sprosen TS, Woodruff GN (1990): Polyamines potentiate NMDA induced whole cell currents in cultured striatal neurons. Eur J Pharmacol 179: 477–478PubMedGoogle Scholar
  86. Stewart GR, Zorumski CF, Price MT, Olney JW (1990): Domoic acid: A dementia-inducing excitotoxic food poison with kainic acid receptor specificity. Exp Neurol 110: 127–138PubMedGoogle Scholar
  87. Tecoma ES, Monyer H, Goldberg MP, Choi DW (1989): Traumatic neuronal injury in vitro is attenuated by NMDA antagonists. Neuron 2: 1541–1545PubMedGoogle Scholar
  88. Teitelbaum JS, Zatorre RJ, Carpenter S, Gendron D, Evans AC, Gjedde A, Cashman NR (1990): Neurologic sequelae of domoic acid intoxication due to the ingestion of contaminated mussels. New Engl J Med 322: 1781–1787PubMedGoogle Scholar
  89. Trussell LO, Thio LL, Zorumski CF, Fischbach GD (1988): Rapid desensitization of glutamate receptors in vertebrate central neurons. Proc Natl Acad Sci USA 85: 2834–2838ADSPubMedGoogle Scholar
  90. Urbanski HF, Ojeda SR (1990): A role for N-methyl-D-aspartate (NMDA) receptors in the control of LH secretion and initiation of female puberty. Endocrinology 126: 1774–1776PubMedGoogle Scholar
  91. Watkins JC, Krogsgaard-Larsen P, Honoré T (1990): Structure-activity relationships in the development of excitatory amino acid receptor agonists and competitive antagonists. Trends Pharmacol Sci 11: 25–33PubMedGoogle Scholar
  92. Weiss JH, Choi DW (1988): Beta-N-Methylamino-L-alanine neurotoxicity: Requirement for bicarbonate as a cofactor. Science 241: 973–975ADSPubMedGoogle Scholar
  93. Weiss JH, Hartley DM, Koh J, Choi DW (1990): The calcium channel blocker nifedipine attenuates slow excitatory amino acid neurotoxicity. Science 247: 1474–1477ADSPubMedGoogle Scholar
  94. Weiss JH, Koh JY, Choi DW (1989): Neurotoxicity of 13-N-methylamino-L-alanine (BMAA) and ß-N-oxalylamino-L-alanine (BOAA) on cultured cortical neurons. Brain Res 497: 64–71PubMedGoogle Scholar
  95. Westbrook GL, Mayer ML (1987): Micromolar concentrations of Zn’ antagonize NMDA and GABA responses of hippocampal neurons. Nature 328: 640–643ADSPubMedGoogle Scholar
  96. Wieloch T (1985): Hypoglycemia induced neuronal damage prevented by an N-methyl-D-aspartate antagonist. Science 230: 681–683ADSPubMedGoogle Scholar
  97. Wieloch T, Engelsen B, Westerberg E, Auer R (1985): Lesions of the glutamatergic cortico-striatal projection in the rat ameliorate hypoglycemic brain damage in the striatum. Neurosci Lett 58: 25–30PubMedGoogle Scholar
  98. Zorumski CF, Thio LL, Clark GD, Clifford DB (1990): Blockade of desensitization augments quisqualate excitotoxicity in hippocampal neurons. Neuron 5: 61–66PubMedGoogle Scholar

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© Birkhäuser Boston 1992

Authors and Affiliations

  • Charles F. Zorumski
  • John W. Olney

There are no affiliations available

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