Neurochemical Research

, Volume 17, Issue 12, pp 1223–1228 | Cite as

Modification of modulatory sites of NMDA receptor in the fetal guinea pig brain during development

  • Om Prakash Mishra
  • Maria Delivoria-Papadopoulos
Original Articles

Abstract

Ontogeny of the NMDA receptor and modification of its modulatory sites in the developing fetus brain was determined. MK-801 binding characteristics in the presence of glycine, glutamate, Mg2+ and spermine were determined and used as an index of NMDA receptor modification. Experiments were performed on guinea pig fetuses at 30, 45, 50, 55, and 60 days (term=63 days) of gestation. The Bmax value increased approximately three-fold from 30 days to 60 days of gestation. The Kd value decreased during the 45–50 day period and then increased toward the end of gestation. The Bmax value reached its maximum level by 55 days of gestation, indicating the presence of a maximum number of NMDA receptors by this age, while the apparent affinity of the receptor showed its peak at 45–50 days of gestation, indicating a potential role for NMDA receptor during the proliferation period of brain development in the guinea pig fetus. The activation of NMDA receptor in the presence of glutamate (10 μM) and glycine (10 μM), as measured by MK-801 binding, was absent at 30 days gestation, with the earliest observation occurring at 35 days gestation. The spermine dependent activation decreased with gestational age. Mg2+ ions increased MK-801 binding in the range of 1–20 μM concentration. Sensitivity to Mg2+ dependent activation increased with the gestational age (from 10 μM Mg2+ at 45 days to 2.5 μM at 55 and 60 days). These results indicate that an increase in number and activation of the NMDA receptor by glutamate and glycine during brain development might increase the susceptibility of the fetal brain to NMDA receptor mediated excitotoxicity as gestation approaches term.

Key Words

NMDA receptor glutamate glycine spermine brain modulatory sites fetus 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Monoghan, D. T., Bridges, R. J., and Cotman, C. W. 1989. The excitatory amino acid receptors: Their classes, pharmacology, and distinct properties in the function of the central nervous system. Annu. Rev. Pharmacol. Toxicol. 29:365–402.Google Scholar
  2. 2.
    Wroblewski, J. T., and Danysz, W. 1989. Modulation of glutamate receptors: Molecular mechanisms and functional implications. Annu. Rev. Pharmacol. Toxicol. 29:441–474.PubMedGoogle Scholar
  3. 3.
    Coolingridge, G. L., and Lester, R. A. J. 1989. Excitatory amino acid receptors in the vertebrate central nervous system. Pharmacological reviews 40(2):143–210.Google Scholar
  4. 4.
    Mayer, M. L., and Westbrook, G. L. 1987. The physiology of excitatory amino acids in the vertebrate central nervous system. Progress in Neurobiology 28:197–276.PubMedGoogle Scholar
  5. 5.
    Wood, P. L., Tadimeti, S. R., Ivengar, S., Lanthorn, T., Monahan, J., Cordi, A., Sun, E., Vasquez, M., Gray, N., and Contreras, P. 1990. A review of the in vitro and in vivo neurochemical characterization of the NMDA/PCP/Glycine/Ion Channel receptor macrocomplex. Neurochem. Res. 15(2):217–230.PubMedGoogle Scholar
  6. 6.
    McDonald, J. W., and Johnston, M. V. 1990. Physiological and pathophysiological roles of excitatory amino acids during central nervous system development. Brain Res. Rev. 15:41–70.PubMedGoogle Scholar
  7. 7.
    Williams, K., Romano, C., and Molinoff, P. B. 1989. Effects of polyamines on the binding of [3H]MK-801 to the N-Methyl-d-aspartate receptor: Pharmacological evidence for the existence of a polyamine recognition site. Mol. Pharm. 36:575–581.Google Scholar
  8. 8.
    Lowry, O. H., Rosenbrough, N. J., Farr, A. L., and Randall, R. J. 1951. Protein measurement with the folin phenol reagent. J. Biol. Chem. 193:265–275.PubMedGoogle Scholar
  9. 9.
    Balazs, R., Jorgensen, O. S., and Hack, N. 1988. N-methyl-d-aspartate promotes the survival of cerebellar granule cells in culture. Neuroscience 27(2):437–451.PubMedGoogle Scholar
  10. 10.
    Balazs, R., Hack, N., and Jorgensen, O. S. 1988. Stimulation of the N-methyl-d-aspartate receptor has a trophic effect of differentiating cerebellar granule cells. Neurosci. Lett. 87:80–86.PubMedGoogle Scholar
  11. 11.
    Nelson, P. G., Brenneman, D. E., Forsythe, I., Nicol, T., and Westbrook, G. 1987. NMDA antagonists increase neuronal death without blocking electrical activity in developing cultures. Soc. Neurosci. Abstr. 13:9.Google Scholar
  12. 12.
    Parnavelas, J. R., Globus, A., and Kaups, P. 1973. Continuous illumination from birth affects spine density of neurons in the visual cortex of the rat. Exp. Neurol. 40:742–747.PubMedGoogle Scholar
  13. 13.
    Collingridge, G. L., and Bliss, T. V. 1987. NMDA receptors-their role in long-term potentiation. Trends Neurosci. 10:288–293.Google Scholar
  14. 14.
    Nicoll, A., Kauer, J. A., and Malenka, R. C. 1988. The current excitement in longterm potentiation. Neuron. 1:97–103.PubMedGoogle Scholar
  15. 15.
    Engelsen, G. 1986. Neurotransmitter glutamate: its clinical importance. Acta Neurol. Scand. 74:337–355.PubMedGoogle Scholar
  16. 16.
    Fonnum, F. 1984. Glutamate: a neurotransmitter in mammalian brain. J. Neurochem. 42:1–11.PubMedGoogle Scholar
  17. 17.
    Watkins, J. C., and Evans, R. H. 1981. Excitatory amino acid transmitters. Ann. Rev. Pharmacol. Toxicol. 21:165–204.Google Scholar
  18. 18.
    Insel, T. R., Miller, L. P., and Gelhard, R. E. 1990. The ontogeny of excitatory amino acid receptors in rat brain-I. N-methyl-d-aspartate and quisqualate receptors. Neurosci. 35:31–43.Google Scholar
  19. 19.
    McDonald, J. W., Johnston, M. V., and Young, A. B. 1990. Differential ontogenic development of three receptors comprising the NMDA receptor/channel complex in the rat hippocampus. Exptl. Neurol. 110:237–247.Google Scholar
  20. 20.
    Ransom, R. W., and Stec, N. L. 1988. Cooperative modulation of3H-MK-801 binding to the N-methyl-d-aspartate receptor-ion channel complex by L-glutamate, glycine and polyamines. J. Neurochem. 51:830–836.PubMedGoogle Scholar
  21. 21.
    Dobbing, J. 1974. The later growth of brain and its vulnerability. Pediatrics 53:2–6.PubMedGoogle Scholar
  22. 22.
    Himwich, W. A. 1962. Biochemical and neurophysiological development of the brain in the neonatal period. 117–158in Pfeiffer, C. S., Smith, J. R. (eds.) International Review of Neurobiology, Vol. 4, Academic Press, New York.Google Scholar
  23. 23.
    Banns, J., Blatehford, D., and Holzbauer, M. 1990. The development of monoamine oxidase, glutamate-dicarboxylase and choline acetyl-transferase in the guinea pig brain. J. Neuroal Transmission 49:21–30.Google Scholar
  24. 24.
    Booth, R. F. G., Patel, T. B., and Clark, J. B. 1980. The development of enzymes of energy metabolism in brain of a precocial (guinea pig) and noncocial (rat) species. J. Neurochem. 43:327–366.Google Scholar
  25. 25.
    Flexner, L. B. 1955. Enzymatic and functional patterns of developing mammalian brain. 281–295,in Waelsch, H. (ed.). biochemistry of the developing nervous system. Academic Press, New York.Google Scholar
  26. 26.
    Himwich, H. E. 1951. Brain metabolism and cerebral disorders. Williams and Wilkins, Baltimore.Google Scholar
  27. 27.
    Mishra, O. P., and Delivoria-Papadopoulos, M. 1988. Na+, K+-ATPase in developing fetal guinea pig brain and the effect of maternal hypoxia. Neurochem. Res. 13(8):765–770.PubMedGoogle Scholar
  28. 28.
    Mishra, O. P., and Delivoria-Papadopoulos, M. 1988. Anti-oxidant enzymes in fetal guinea pig brain during development and the effect of maternal hypoxia. Devel. Brain Res. 42:173–179.Google Scholar
  29. 29.
    Mishra, O. P., Wagerle, L. C., and Delivoria-Papadopoulos, M. 1988. 5′-Nucleotidase and adenosine deaminase in developing fetal guinea pig brain and the effect of maternal hypoxia. Neurochem. Res. 13(11):1055–1060.PubMedGoogle Scholar
  30. 30.
    Dobbing, J., and Sands, J. 1970. Growth and development of the brain and spinal cord of the guinea pig. Brain Res. 17:115–123.PubMedGoogle Scholar
  31. 31.
    Dobbing, J., and Smart, J. L. 1974. Vulnerability of brain and behavior. Br. Med. Bull. 30:164–168.PubMedGoogle Scholar
  32. 32.
    Nowak, L., Bergestovski, P., Ascher, P., Herbet, A., and Prochiantz, A. 1984. Magnesium gates glutamate-activated channels in mouse central neurons. Nature 307:462–465.PubMedGoogle Scholar
  33. 33.
    Mayer, M. L., Westbrook, G. L., and Guthrie, P. B. 1984. Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature 309:261–263.PubMedGoogle Scholar
  34. 34.
    Reynolds, I. J., and Miller, R. J. 1988 (3H)MK-801 binding to the NMDA receptor/ionophore complex is regulated by divalent cations: evidence for multiple regulatory sites. Eur. J. Pharmacol. 151:103–112.PubMedGoogle Scholar
  35. 35.
    Mishra, O. P., and Delivoria-Papadopoulos, M. 1989. Lipid peroxidation in developing fetal guinea pig brain during normoxia and hypoxia. Devel. Brain Res. 45:129–135.Google Scholar

Copyright information

© Plenum Publishing Corporation 1992

Authors and Affiliations

  • Om Prakash Mishra
    • 1
  • Maria Delivoria-Papadopoulos
    • 1
  1. 1.Department of PhysiologyUniversity of Pennsylvania School of MedicinePhiladelphia

Personalised recommendations