Abstract
Increasing evidence indicates that the GABAergic system in cerebellar and limbic structures is affected in autism. We extended our previous study that found reduced [3H]flunitrazepam-labeled benzodiazepine sites in the autistic hippocampus to determine whether this reduction was due to a decrease in binding site number (B max) or altered affinity (K d) to bind to the ligand. Quantitation of hippocampal lamina demonstrated a 20% reduction in B max indicating a trend toward a decreased number of benzodiazepine binding sites in the autistic group but normal K d values. A reduction in the number of hippocampal benzodiazepine binding sites suggests alterations in the modulation of GABAA receptors in the presence of GABA in the autistic brain, possibly resulting in altered inhibitory functioning of hippocampal circuitry.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
American Psychiatric Association (1994). Diagnostic and statistical manual of mental disorders (DSM-IV) (4th ed.). Washington, DC: American Psychiatric Press.
Arin, D. M., Bauman, M. L., & Kemper, T. L. (1991). The distribution of Purkinje cell loss in the cerebellum in autism (abstract). Neurology, 41, 307.
Babb, T. L., Pretorius, J. K., Kupfer, W. R., & Crandell, P. H. (1989) Glutamate decarboxylase-immunoreactive neurons are preserved in human epileptic hippocampus. Journal of Neuroscience, 9, 2562–2574.
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.
Barker, J. L., Behar, T. N., Ma, W., Maric, D., & Maric, I. (2000). GABA emerges as a developmental signal during neurogenesis of the rat central nervous system. In D. L. Martin, & R. W. Olsen (Eds.), GABA in the nervous system: The view at fifty years (pp. 245–263, Ch. 15). Philadelphia: Lippincott Williams and Wilkins.
Bauman, M. L., & Kemper, T. L. (1994). Neuroanatomic observations of the brain in autism. In M. L. Bauman, & T. L. Kemper (Eds.), The Neurobiology of autism (pp. 119–145). Baltimore: Johns Hopkins University Press.
Bauman, M. L., & Kemper, T. L. (1985). Histoanatomic observations of the brain in early infantile autism. Neurology, 35, 866–874.
Blatt, G. J., Fitzgerald, C. M., Guptill, J. T., Booker, A. B., Kemper, T. L, & Bauman, M. L. (2001). Density and distribution of hippocampal neurotransmitter receptors in autism: An autoradiographic study. Journal of Autism and Developmental Disorders, 31, 537–543.
Dennis, T., Dubois, A., Benavides, J., & Scatton, B. (1988). Distribution of central ω1 (benzodiazepine1) and ω2 (benzodiazepine2) receptor subtypes in the monkey and human brain. An autoradiographic study with [3H]flunitrazepam and the ω1 selective ligand [3H]zolpidem. Journal of Pharmacolology and Experimental Therapeutics, 247, 309–322.
Fatemi, S. H., Halt, A. R., Stary, J. M., Kanodia, R., Schulz, S. C., & Realmuto, G. R. (2002). Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biological Psychiatry, 52, 805–810.
Freund, J. (1988). Analysis of variance. In N. Romanelli (Ed.), Modern elementary statistics (7th ed., pp. 380–414). Englewood Cliffs: Prentice Hall.
Fritschy, J.-M., Kiener, T., Bouilleret, V., & Loup, F. (1999). GABAergic neurons and GABAA-receptors in temporal lobe epilepsy. Neurochemistry International, 34, 435–445.
Fritschy, J.-M., & Brunig, I. (2003). Formation and plasticity of GABAergic synapses: Physiological mechanisms and pathophysiological implications. Pharmacology Therapeutics, 98, 299–323.
Geary, W. A., & Wooten, G. F. (1983). Quantitative film autoradiography of opiate agonist and antagonist binding in rat brain. Journal of Pharmacology and Experimental Therapeutics, 225, 234–240.
Gillberg, C., Steffenburg, S., & Jakobsson, G. (1987). Neurobiological findings in 20 relatively gifted children with Kanner-type autism or Asperger syndrome. Developmental Medicine & Child Neurology, 29, 641–649.
Goode, S., Rutter, M., & Howlin, P. (1994). A twenty year follow-up of children with autism. In 13th biennial meeting of ISSBD. Amsterdam, The Netherlands.
Houser, C. R., Miyashiro, J. E., Swartz, B. E., Walsh, G. O., Rich, J. R., & Delgado-Escueta, A. V. (1990). Altered patterns of dynorphin immunoreactivity suggest mossy fiber reorganization in human hippocampal epilepsy. Journal of Neuroscience, 10, 267–282.
Kemper, T. L., & Bauman, M. L. (1998). Neuropathology of infantile autism. Journal of Neuropathology & Experimental Neurology, 57, 645–652.
Lawrence, Y., Kemper, T. L., Bauman, M. L., & Blatt, G. J. (2004). Increased density of parvalbumin labeled hippocampal interneurons in autism. International Meeting for Autism Research Abstracts, 3, 45–46.
Matheja, P., Ludemann, P., Kuwert, T., Weckesser, M., Kellinghaus, C., Weitemeyer, L., Diehl, B., Schuierer, G., Ringelstein, E. B., & Schober, O. (2001). Disturbed benzodiazepine receptor function at the onset of temporal lobe epilepsy. Journal of Neurology, 248, 585–591.
Mohler, H., Benke, B., Benson, J., Luscher, B., Rudolph, U., & Fritschy, J. M. (1997). Diversity in structure, pharmacology and regulation of GABAA receptors. In S. J. Enna, & N. G. Bowery (Eds.), The GABA receptors (pp. 11–36, Ch. 2). Totawa, NJ: Humana Press.
Mohler, H., Benke, D., Fritschy, J. M., & Benson, J. (2000). The benzodiazepine site of GABAA receptors. In D. L. Martin, & R. W. Olsen (Eds.), GABA in the nervous system: The view at fifty years (pp. 97–112, Ch. 7). Philadelphia: Lippincott Williams and Wilkins.
Mohler, H., Fritschy, J. M., Crestani, F., Hensch, T., & Rudolph, U. (2004). Specific GABAA circuits in brain development and therapy. Biochemical Pharmacology, 68, 1685–1690.
Nurmi, E. L., Dowd, M., Tadevosyan-Leyfer, O., Haines, J. L., Folstein, S. E., & Sutcliffe, J. S. (2003). Exploratory subsetting of autism families based on savant skills improves evidence of genetic linkage to 15q11-q13. Journal of American Academy of Adolescent Psychiatry, 42, 856–863.
Olsson, I., Steffenburg, S., & Gillberg, C. (1988). Epilepsy in autism and autistic-like conditions: A population based study. Archives of Neurology, 45, 666–668.
Raymond, G. V., Bauman, M. L., & Kemper, T. L. (1996). Hippocampus in autism: A Golgi analysis. Acta Neuropathologica, 91, 117–119.
Ritvo, E. R., Freeman, B. J., Scheibel, A. B., Duong, T., Robinson, H., 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.
Rosene, D. L., & Van Hoesen, G. W. (1987). The hippocampal formation of the primate brain: A review of some comparative aspects of cytoarchitecture and connections. In E. G. Jones, & A. Peters (Eds.), Cerebral cortex (Vol. 6, pp. 345–456). New York: Plenum Press.
Rutter, M. (1970). Autistic children: Infancy to adulthood. Seminars in Psychiatry, 2, 435–450.
Savic, I., Persson, A., & Roland, P. (1988). In vivo demonstration of reduced benzodiazepine receptor binding in human epileptic foci. Lancet, 2, 863–866.
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.
Shao, Y., Cuccaro, M. L., Hauser, E. R., Raiford, K. L., Menold, M. M., Wolpert, C. M., Ravan, S. A., Elston, L., Decena, K., Donnelly, S. L., Abramson, R. K., Wright, H. H., DeLong, G. R., Golbert, J. R., & Pericak-Vance, M. A. (2003). Fine mapping of autistic disorder to chromosome 15q11-q13 by use of phenotypic subtypes. American Journal of Human Genetics, 72, 539–548.
Shaw, C., Aoki, C., Wilkinson, M., Prusky, G., & Cynader, M. (1987). Benzodiazepine ([3H]flunitrazepam) binding in cat visual cortex: Ontogenesis of normal characteristics and the effects of dark rearing. Developmental Brain Research, 37, 67–76.
Volkmar, F. R., & Nelson, I. (1990). Seizure disorders in autism. Journal of the American Academy of Adolescent Psychiatry, 29, 127–129.
Werck, M. C., & Daval, J. L. (1991). Autoradiographic changes in central benzodiazepine binding sites and their coupling to gama-aminobutyric acid receptors after seizures in the developing rat. Pediatric Research, 30, 100–105.
Whitney, E. R., Kemper, T. L., Bauman, M. L., & Blatt, G. J. (2004). Calbindin D-28K is a reliable marker for cerebellar Purkinje cells in control and autistic cerebellum. International Meeting for Autism Research (IMFAR) abstract, 3, 153.
Yip, J., Soghomonian, J.-J., Nguyen, L. T., & Blatt, G. J. (2005). Decreased GAD67 in Purkinje cells in the posterolateral cerebellar cortex in autism: An in situ hybrization study. Society for Neuroscience abstract, 35, 603.8.
Acknowledgments
This research was supported by NIH NINDS NS38975-01A1 (Dr. Margaret L. Bauman, P.I.). Brain tissue was provided by the Harvard Brain Tissue Resource Center (HBTRC) (Francine Benes, M.D., Ph.D., Director) and from the Autism Tissue Program (ATP) (Jane Pickett, Ph.D., Director) via the University of Miami and the University of Maryland Brain Banks. The authors would like to thank Dr. Susan Blease and Claudia Fitzgerald for their help with tissue processing.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Guptill, J.T., Booker, A.B., Gibbs, T.T. et al. [3H]-Flunitrazepam-labeled Benzodiazepine Binding Sites in the Hippocampal Formation in Autism: A Multiple Concentration Autoradiographic Study. J Autism Dev Disord 37, 911–920 (2007). https://doi.org/10.1007/s10803-006-0226-7
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10803-006-0226-7