Advertisement

Journal of Autism and Developmental Disorders

, Volume 31, Issue 6, pp 537–543 | Cite as

Density and Distribution of Hippocampal Neurotransmitter Receptors in Autism: An Autoradiographic Study

  • Gene J. Blatt
  • Claudia M. Fitzgerald
  • Jeffrey T. Guptill
  • Anne B. Booker
  • Thomas L. Kemper
  • Margaret L. Bauman
Article

Abstract

Neuropathological studies in autistic brains have shown small neuronal size and increased cell packing density in a variety of limbic system structures including the hippocampus, a change consistent with curtailment of normal development. Based on these observations in the hippocampus, a series of quantitative receptor autoradiographic studies were undertaken to determine the density and distribution of eight types of neurotransmitter receptors from four neurotransmitter systems (GABAergic, serotoninergic [5-HT], cholinergic, and glutamatergic). Data from these single concentration ligand binding studies indicate that the GABAergic receptor system (3[H]-flunitrazepam labeled benzodiazepine binding sites and 3[H]-muscimol labeled GABAA receptors) is significantly reduced in high binding regions, marking for the first time an abnormality in the GABA system in autism. In contrast, the density and distribution of the other six receptors studied (3[H]-8OH-DPAT labeled 5-HT1A receptors, 3[H]-ketanserin labeled 5-HT2 receptors, 3[H]-pirenzepine labled M1 receptors, 3[H]-hemicholinium labeled high affinity choline uptake sites, 3[H]-MK801 labeled NMDA receptors, and 3[H]-kainate labeled kainate receptors) in the hippocampus did not demonstrate any statistically significant differences in binding.

Autism GABAA receptors benzodiazepine receptors serotoninergic receptors cholinergic receptors hippocampus 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

REFERENCES

  1. Arin, D. M., Bauman, M. L., & Kemper, T. L. (1991). The distribution of Purkinje cell loss in the cerebellum in autism. Neurology, 41, 307.Google Scholar
  2. Bailey, A., Luthert, P., Dean, A., Harding, B., Janota, I., Montgomery, M., Rutter, M., & Lantos, P. (1998). A clinicopathological study of autism. Brain, 121, 889–905.Google Scholar
  3. Barker, J. L., Behar, T., Li, Y-X., Liu, Q-Y., Ma, W., Maric, D., Maric, I., Schaffner, A. E., Serafini, R., Smith, S. V., Somogyi, R., Vautrin, J. Y., Wen, X-L., & Xian, H. (1998). GABAergic cells and signals in CNS development. Perspective Development in Neurobiology, 5, 305–322.Google Scholar
  4. Bauman, M. L., & Kemper, T. L. (1985). Histoanatomic observations of the brain in early infantile autism. Neurology, 35, 866–874.PubMedGoogle Scholar
  5. Bauman, M. L., & Kemper, T. L. (1994). Neuroanatomic observations of the brain in autism. In Bauman, M. L., & Kemper, T. L. (eds.), The Neurobiology of Autism. (pp. 119–145), Baltimore: Johns Hopkins University Press.Google Scholar
  6. Ben-Ari, Y., Khazipov, R., Leinekugel, R., Caillard, O., & Gaiarsa, J-L. (1997). GABAA, NMDA, and AMPA receptors: A developmentally regulated 'menage a trois'. TINS, 20, 523–529.PubMedGoogle Scholar
  7. Cherubini, E., Gaiarsa, J. L., & Ben-Ari, Y. (1991). GABA: An excitatory transmitter in early postnatal life. TINS, 14, 515–519.PubMedGoogle Scholar
  8. Cook, E. H., Courchesne, R. Y., Cox, N. J., Lord, C., Gonen, D., Guter, S. J., Lincoln, A., Nix, K., Haas, R., Leventhal, B. L., & Courchesne, E. (1998). Linkage-disequilibrium mapping of autistic disorder, with 15q11–13 markers. American Journal of Human Genetics, 62, 1077-1083.PubMedGoogle Scholar
  9. Daval, J-L., Werck, M-C., Nehlig, A., & Vasconcelos, A. P. (1991). Quantitative autoradiographic study of the postnatal development of benzodiazepine binding sites and their coupling to GABA receptors in the rat brain. International Journal of Developmental Neuroscience, 9, 307–320.PubMedGoogle Scholar
  10. Dennis, T., Dubois, A., Benavides, J., & Scatton, B. (1988). Distribution of central v1 (benzodiazepine1) and ?2 (benzodiazepine2) receptor subtypes in the monkey and human brain. An autoradiographic study with [3H]flunitrazepam and the w1 selective ligand [3H]zolpidem. Journal of Pharmacology and Experimental Therapy., 247(1), 309–322.Google Scholar
  11. Faull, R. L. M., Villiger, J. W., & Holford, N. H. G. (1987). Benzodiazepine receptors in the human cerebellar cortex: A quantitative autoradiographic and pharmacological study demonstrating the predominance of type I receptors. Brain Research, 411, 379–385.PubMedGoogle Scholar
  12. Faull, R. L. M., & Villiger, J. W. (1988). Benzodiazepine receptors in the human hippocampal formation: A pharmacological and quantitative autoradiographic study. Neuroscience, 26, 783–790.PubMedGoogle Scholar
  13. Fernandez-Lopez, A., Chinchetru, M. A., & Fernandez, P. C. (1997). The autoradiographic perspective of central benzodiazepine receptors: A short review. General Pharmacology, 29, 173–180.PubMedGoogle Scholar
  14. Freund, J. (1988). Analysis of variance. In Modern Elementry Statistics, (7th ed.), (pp. 380–414), Romanelli, N. (Ed.), Englewood Cliffs: Prentice-Hall.Google Scholar
  15. Geary, W. A., & Wooten, G. F. (1983). Quantitative film autoradiography of opiate agonist and antagonist binding in rat brain. Brain Research, 225, 234–240.Google Scholar
  16. Hammer, R., Berrie, C. P., Birdsall, N. J. M., Burgen, A. S. V., & Hulme, E. C. (1980). Pirenzepine distinguishes between different subclasses of muscarinic receptors. Nature, 283, 90–92.PubMedGoogle Scholar
  17. Kemper, T. L., & Bauman, M. L. (1992). Neuropathology of infantile autism. In N. Naruse & E. M. Ornitz (Eds.), Neurobiology of Infantile Autism (pp. 43–57), Amsterdam: Elsevier.Google Scholar
  18. Kemper, T. L., & Bauman, M. L. (1998). Neuropathology of infantile autism. Journal of Neuropathology and Experimental Neurology, 57, 645–652.PubMedGoogle Scholar
  19. Lidow, M. S., Goldman-Rakic, P. S., Gallager, D. W., & Rakic, P. (1989). Quantitative autoradiographic mapping of serotonin 5-HT1 and 5-HT2 receptors and uptake sites in the neocortex of the rhesus monkey. Journal of Comparative Neurology, 280, 27–42.PubMedGoogle Scholar
  20. Marrosu, F., Marrosu, G., Rachel, M. G., & Biggio, G. (1987). Paradoxical reactions elicited by diazepam in children with classic autism. Functional Neurology, 2, 355–361.PubMedGoogle Scholar
  21. Mohler, H., Benke, D., Fritschy, J. M., & Benson, J. (2000). The benzodiazepine site of GABAA receptors. In GABA in the Nervous System: The View at Fifty Years, (pp. 97–112), Martin, D. L. & Olsen, R. W. (Eds.), Philadelphia: Lippincott Williams and Wilkens.Google Scholar
  22. Monaghan, D. T. (1991). Differential stimulation of [3H]-MK-801 binding to subpopulations of NMDA receptors. Neuroscience Letters, 122, 21–24.PubMedGoogle Scholar
  23. Monaghan, D. T., Yao, D., & Cotman, C. W. (1986). The distribution of [3H]kainate binding sites in primate hippocampus is similar to the distribution of both Ca++ sensitive and Ca++ insensitive [3H]kainate binding sites in rat hippocampus. Neurochemical Research, 11, 1073–1082.PubMedGoogle Scholar
  24. Olsen, R. W., & Tobin, A. J. (1990). Molecular biology of GABAA receptors. FASEB Journal, 4, 1469–1480.PubMedGoogle Scholar
  25. Palacios, J. M., Wamsley, J. K., & Kuhar, M. J. (1981). High affinity GABA receptors-autoradiographic localization. Brain Research, 222, 285–307.PubMedGoogle Scholar
  26. Pazos, A., & Palacios, M. (1985). Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors. Brain Research, 346, 205–230.PubMedGoogle Scholar
  27. Penney, J. B., & Young, A. B. (1982). Quantitative autoradiography of neurotransmitter receptors in Huntington's disease. Neurology, 32, 1391–1395.PubMedGoogle Scholar
  28. Rabow, L. E., Russek, S. J., & Farb, D. H. (1995). From ion currents to genomic analysis: Recent advances in GABAA receptor research. Synapse, 21, 189–274.PubMedGoogle Scholar
  29. Raymond, G., Bauman, M. L., & Kemper, T. L. (1996). Hippocampus in autism: A Golgi study. Acta Neuropathology, 91, 117–119.Google Scholar
  30. Ritvo, E. R., Freeman, B. J., Schiebel, A. B., Robinson, D. T., Guthrie, D., & Ritvo, A. (1986). Lower Purkinje cell counts in the cerebella of four autistic subjects: Initial findings of the UCLA-NSAC autopsy research report. American Journal of Psychiatry, 146, 862–866.Google Scholar
  31. Sandberg, K., & Coyle, J. T. (1985). Characterization of [3H] hemicholinium-3 binding associated with neuronal choline uptake sites in rat brain membranes. Brain Research, 348, 321–330.PubMedGoogle Scholar
  32. Schroer, R. J., Phelan, M. C., Michaelis, R. C., Crawford, E. C., Skinner, S. A., Cuccaro, M., Simensen, R. J., Bishop, J., Skinner, C., Fender, D., & Stevenson, R. E. (1998). Autism and maternally derived aberrations of chromosome 15q. American Journal of Medical Genetics, 76, 327–336.PubMedGoogle Scholar
  33. Speth, R. C., Wastek, G. J., Johnson, P. C., & Yamamura, H. I. (1978). Benzodiazepine binding in human brain: Characterization using [3H]-flunitrazepam, Life Science, 22, 859–866.Google Scholar
  34. Watson, S., & Girdlestone, D. (1996). Receptor and ion channel nomenclature. TIPS (Suppl 7), 37–38.Google Scholar
  35. Whiting, P. J., Wafford, K. A., & McKernan, R. M. (2000). Pharmacologic subtypes of GABAA receptors based on subunit composition. In GABA in the Nervous System: The View at Fifty Years, (pp. 113–126), Martin, D. L., & Olsen, R. W. (Eds.), Philadelphia: Lippincott Williams and Wilkens.Google Scholar
  36. Young, W. S. III, & Kuhar, M. J. (1979). Autoradiographic localization of benzodiazepine receptors in the brains of humans and animals. Nature, 280, 393–439.Google Scholar

Copyright information

© Plenum Publishing Corporation 2001

Authors and Affiliations

  • Gene J. Blatt
    • 1
  • Claudia M. Fitzgerald
    • 1
  • Jeffrey T. Guptill
    • 1
  • Anne B. Booker
    • 1
  • Thomas L. Kemper
    • 1
  • Margaret L. Bauman
    • 1
  1. 1.Neurobiology of Developmental Disorders Laboratory, Department of Anatomy and NeurobiologyBoston University School of MedicineUSA

Personalised recommendations