Excitatory Amino Acids, Growth Factors, and Calcium: A Teeter-Totter Model for Neural Plasticity and Degeneration

  • Mark P. Mattson
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 268)


This paper presents and examines the hypothesis that excitatory amino acids (EAAs) and growth factors (GFs) exert opposing actions on neuronal cytoarchitecture by influencing cellular Ca2+homeostasis. This hypothesis is supported by experiments with cultured hippocampal pyramidal neurons in which EAAs induced dendritic regression and cell death, whereas fibroblast GF (FGF) promoted neurite outgrowth and cell survival. FGF protected against glutamate-induced neuronal degeneration by raising the threshold for the actions of this EAA. Pharmacological studies, and direct monitoring of intracellular Ca2+ levels, demonstrated that a sustained rise in intracellular Ca2+ levels was largely responsible for the degenerative actions of glutamate. FGF attenuated the Ca2 + response to glutamate. Experiments with glutamate, Ca2+ ionophore A23187, and Na+-deficient culture medium provided evidence that FGF can enhance Na+-dependent Ca2+ extrusion. These data suggest a model in which cell survival and neurite outgrowth in hippocampal neurons is regulated by the opposing actions of EAAs and GFs acting through the Ca2+ second messenger system. In this “teeter-totter” model the relative levels of input from EAAs and GFs determine whether a neuron lives or dies, and whether its outgrowth is in a progressive or regressive state. Interactions of EAAs and GFs may play important roles in: developmental events such as neu-rite outgrowth, synaptogenesis, and natural cell death; maintenance and plasticity of neural circuitry in the mature nervous system; and maladaptive neurodegeneration that occurs in aging and disorders such as Alzheimer’s disease.


Amyotrophic Lateral Sclerosis Nerve Growth Factor Hippocampal Neuron Pyramidal Neuron Neurite Outgrowth 
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.


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  1. 1.
    Alkon, D. L., 1989, Memory storage and neural system. Sci. Amer. 261: 42–50.Google Scholar
  2. 2.
    Appel, S. H., 1986, A unifying hypothesis for the cause of amyotrophic lateral sclerosis, Parkinsonism, and Alzheimer disease. Ann. Neurol. 10: 499–505.Google Scholar
  3. 3.
    Caday, C. G., A. Mirzabegian, J. Prosser, M. Klagsbrun and S. P. Finklestein., 1988, Fibroblast growth factor levels in developing brain. Soc. Neurosci. Abstr. 14: 363.Google Scholar
  4. 4.
    Carafoli, E., 1987, Intracellular calcium homeostasis. Ann. Rev. Biochem. 56: 395–433.Google Scholar
  5. 5.
    Choi, D. W., 1988, Glutamate neurotoxicity and diseases of the nervous system. Neuron 1: 623–634.PubMedCrossRefGoogle Scholar
  6. 6.
    Connor, J. A., W. J. Wadman, P. E. Hockberger and R. K. S. Wong., 1988, Sustained dendritic gradients of calcium induced by excitatory amino acids in CAl hippocampal neurons. Science 240: 649–653.PubMedCrossRefGoogle Scholar
  7. 7.
    Cowan, W. M., J. W. Fawcett, D. D. M. O’Leary, and B. B. Stanfield. 1984. Regressive events in neurogenesis. Science 225: 1258–1265.PubMedCrossRefGoogle Scholar
  8. 8.
    Deyo, R. A., K. T. Straube, and J. F. Disterhoft. 1989. Nimodipine facilitates associative learning in aging rabbits. Science 243: 809–811.PubMedCrossRefGoogle Scholar
  9. 9.
    Dreyer, D., A. Lagrange, C. Grothe and K. Unsicker., 1989, Basic fibroblast growth factor prevents ontogenetic neuron death in vivo. Neurosci. Lett. 99: 35–38.Google Scholar
  10. 10.
    Fischer, W. K. Wictorin, A. Bjorklund, L. R. Williams, S. Varon and F. H. Gage., 1987, Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor. Nature 329: 65–68.PubMedCrossRefGoogle Scholar
  11. 11.
    Gage, F. H., D. M. Armstrong, L. R. Williams and S. Varon., 1988, Morphological response of axotomized septal neurons to nerve growth factor. J. Comp. Neurol. 269: 147–155.Google Scholar
  12. 12.
    Gibson, G. E., and C. Peterson., 1987, Calcium and the aging nervous system. Neurobiol. Aging 8: 329–343.Google Scholar
  13. 13.
    Green, L. A., and E. M. Shooter., 1980, The nerve growth factor. Annu. Rev. Neurosci. 4: 353–402.CrossRefGoogle Scholar
  14. 14.
    Hefti, F., A. Dravid and J. Hartikka., 1984, Chronic intraventricular injections of nerve growth factor elevate hippocampal choline acetyltransferase activity in adult rats with partial septo-hippocampal lesions. Brain Res. 293: 305–311.PubMedCrossRefGoogle Scholar
  15. 15.
    Hesketh, T. R., J. P. Moore, J. D. H. Morris, M. V. Taylor, J. Rogers, G. A. Smith and J. C. Metcalfe., 1985, A common sequence of calcium and pH signals in the mitogenic stimulation of eukaryotic cells. Nature 313: 481–484.PubMedCrossRefGoogle Scholar
  16. 16.
    Kater, S. B., M. P. Mattson, C. S. Cohan, and J. A. Connor., 1988, Calcium regulation of the neuronal growth cone. Trends Neurosci. 11: 315–321.PubMedCrossRefGoogle Scholar
  17. 17.
    Kudo, Y., K. Ito, H. Miyakawa, Y. Izumi, A. Ogura and H. Kato., 1987, Cytoplasmic calcium elevation in hippocampal granule cell induced by perforant path stimulation and L-glutamate application. Brain Res. 407: 168–172.PubMedCrossRefGoogle Scholar
  18. 18.
    Maragos, W. F., J. T. Greenamyre, J. B. Penney, and A. B. Young., 1987, Glutamate dysfunction in Alzheimer’s disease: an hypothesis. Trends Neurosci. 10: 65–68.CrossRefGoogle Scholar
  19. 19.
    Mattson, M. P., 1988, Neurotransmitters in the regulation of neuronal cytoarchitecture. Brain Res. Rev. 13: 179–212.CrossRefGoogle Scholar
  20. 20.
    Mattson, M. P., 1989, Cellular signaling mechanisms common to the development and degeneration of neuroarchitecture. Mech. Ageing Dev in pressGoogle Scholar
  21. 21.
    Mattson, M. P, P. Dou, and S. B. Kater., 1988, Outgrowth-regulating actions of glutamate in isolated hippocampal pyramidal neurons. J. Neurosci. 8: 2087–2100.Google Scholar
  22. 22.
    Mattson, M. P., P. b. Guthrie, B. C. Hayes, and S. B. Kater., 1989, Roles for mitotic history in the generation and degeneration of neuroarchitecture. J. Neurosci. 9: 1223–1232.Google Scholar
  23. 23.
    Mattson, M. P., P. B. Guthrie, and S. B. Kater., 1988, Intracellular messengers in the generation and degeneration of hippocampal neuroarchitecture. J. Neurosci. Res. 20: 447–464.Google Scholar
  24. 24.
    Mattson, M. P., P. B. Guthrie, and S. B. Kater. 1989. A role for Na+-dependent calcium extrusion in protection against neuronal excitotoxicity. FASEB J in press.Google Scholar
  25. 25.
    Mattson, M. P., and S. B. Kater., 1989, Development and selective neurodegeneration in cell cultures from different hippocampal regions. Brain Res. 490: 110–125.PubMedCrossRefGoogle Scholar
  26. 26.
    Mattson, M. P., R. E. Lee, M. E. Adams, P. B. Guthrie, and S. B. Kater., 1988, Interactions between entorhinal axons and target hippocampal neurons: A role for glutamate in the development of hippocampal circuitry. Neuron 1: 865–876.Google Scholar
  27. 27.
    Mattson, M. P., M. Murrain, P. B. Guthrie, and S. B. Kater., 1989, Fibroblast growth factor and glutamate: Opposing roles in the generation and degeneration of hippocampal neuroarchitecture. J. Neurosci 9: in pressGoogle Scholar
  28. 28.
    Morrison, R. S., R. F. Keating and J. R. Moskal., 1988, Basic fibroblast growth factor and epidermal growth factor exert differential trophic effects on CNS neurons. J. Neurosci. Res. 21: 71–79.Google Scholar
  29. 29.
    Otto, D., M. Frotscher and K. Unsicker., 1989, Basic fibroblast growth factor and nerve growth factor administered in gel foam rescue medial septal neurons after fimbria fornix transection. J. Neurosci. Res. 22: 83–91.Google Scholar
  30. 30.
    Pettmann, B., G. Labourdette, M. Weibel and M. Sensenbrenner., 1986, The brain fibroblast growth factor (FGF) is localized in neurons. Neurosci. Lett. 68: 175–180.Google Scholar
  31. 31.
    Repress, A, E. Tremblay, and Y. Ben-Ari., 1989, Transient increase of NMDA-binding sites in human hippocampus during development. Neurosci. Lett. 99: 61–66.Google Scholar
  32. 32.
    Rozengurt, E. and S. A. Mendoza., 1985, Synergistic signals in mitogenesis: Role of ion fluxes, cyclic nucleotides and protein kinase C in Swiss 3T3 cells. J. Cell Sci. 3Google Scholar
  33. suppl.):229–242.Google Scholar
  34. 33.
    Schwarcz, R., A. C. Foster, E. D. French, W. O. Whetsell, and C. Kohler., 1984, Excitotoxic models for neurodegenerative disorders. Life Sci. 35: 19–32.PubMedCrossRefGoogle Scholar
  35. 34.
    Tulipan, N., S. Luo, G. S. Allen and W. O. Whetsell., 1988, Striatal grafts provide sustained protection from kainic and quinolinic acid-induced damage. Expl. Neurol. 102: 325–332.Google Scholar
  36. 35.
    Walicke, P. A., 1988, Basic and acidic fibroblast growth factors have trophic effects on neurons from multiple CNS regions. J. Neurosci. 8: 2618–2627.Google Scholar

Copyright information

© Springer Science+Business Media New York 1990

Authors and Affiliations

  • Mark P. Mattson
    • 1
  1. 1.Sanders-Brown Research Center on Aging and Department of Anatomy & NeurobiologyUniversity of Kentucky Medical CenterLexingtonUSA

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