Skip to main content
Log in

GABAA Receptor Downregulation in Brains of Subjects with Autism

  • Original Paper
  • Published:
Journal of Autism and Developmental Disorders Aims and scope Submit manuscript

Abstract

Gamma-aminobutyric acid A (GABAA) receptors are ligand-gated ion channels responsible for mediation of fast inhibitory action of GABA in the brain. Preliminary reports have demonstrated altered expression of GABA receptors in the brains of subjects with autism suggesting GABA/glutamate system dysregulation. We investigated the expression of four GABAA receptor subunits and observed significant reductions in GABRA1, GABRA2, GABRA3, and GABRB3 in parietal cortex (Brodmann’s Area 40 (BA40)), while GABRA1 and GABRB3 were significantly altered in cerebellum, and GABRA1 was significantly altered in superior frontal cortex (BA9). The presence of seizure disorder did not have a significant impact on GABAA receptor subunit expression in the three brain areas. Our results demonstrate that GABAA receptors are reduced in three brain regions that have previously been implicated in the pathogenesis of autism, suggesting widespread GABAergic dysfunction in the brains of subjects with autism.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Abdolmaleky, H. M., Cheng, K. H., Russo, A., Smith, C. L., Faraone, S. V., Wilcox, M., et al. (2005). Hypermethylation of the Reelin (RELN) promoter in the brain of schizophrenic patients: A preliminary report. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 134B, 60–66. doi:10.1002/ajmg.b.30140.

    Article  Google Scholar 

  • Akbarian, S., Kim, J. J., Potkin, S. G., Hagman, J. O., Tafazzoli, A., Bunney, W. E., Jr., et al. (1995). Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Archives of General Psychiatry, 52, 258–266.

    PubMed  Google Scholar 

  • American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: APA Press.

    Google Scholar 

  • Bauman, M. L., & Kemper, T. L. (Eds.). (1994). Neuroanatomic observations of the brain in autism. In The neurobiology of autism (pp. 19–145). Baltimore, MD: Johns Hopkins University Press.

  • Bauman, M. L., & Kemper, T. L. (Eds.). (2005). Structural brain anatomy in autism: What is the evidence? In The neurobiology of autism (pp. 121–135). Baltimore, MD: Johns Hopkins University Press.

  • Binnie, C. D. (1993). Significance and management of transitory cognitive impairment due to subclinical EEG discharges in children. Brain and Development, 15, 23–30.

    Google Scholar 

  • 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, 537–544. doi:10.1023/A:1013238809666.

    Article  PubMed  Google Scholar 

  • Brandon, N. J., Smart, T. G., & Moss, S. J. (2000). Regulation of GABAA receptors by protein phosphorylation. In D. Martin & R. Olsen (Eds.), GABA in the nervous system: The view at fifty years (pp. 191–206). Philadelphia, PA: Lippincott, Williams and Wilkins.

    Google Scholar 

  • Buxhoeveden, D. P., Semendeferi, K., Schenker, N., & Courchesne, E. (2004). Decreased cell column spacing in autism. Program and abstracts of the Society for Neuroscience 34th Annual Meeting, San Diego, California. Abstract 582.6.

  • Canitano, R. (2007). Epilepsy in autism spectrum disorders. European Child and Adolescent Psychiatry, 16, 61–66.

    Google Scholar 

  • Carper, R., & Courchesne, E. (2005). Localized enlargement of the frontal lobe in autism. Biological Psychiatry, 57, 126–133. doi:10.1016/j.biopsych.2004.11.005.

    Article  PubMed  Google Scholar 

  • Carper, R. A., Moses, P., Tigue, Z. D., & Courchesne, E. (2002). Cerebral lobes in autism: Early hyperplasia and abnormal age effects. NeuroImage, 16, 1038–1051. doi:10.1006/nimg.2002.1099.

    Article  PubMed  Google Scholar 

  • Casanova, M. F., Buxhoeveden, D. P., & Brown, C. (2002). Clinical and macroscopic correlates of minicolumnar pathology in autism. Journal of Child Neurology, 17, 692–695.

    Google Scholar 

  • Courchesne, E., & Pierce, K. (2005). Why the frontal cortex in autism might be talking only to itself: Local over-connectivity but long-distance disconnection. Current Opinion in Neurobiology, 15, 225–230. doi:10.1016/j.conb.2005.03.001.

    Article  PubMed  Google Scholar 

  • Courchesne, E., Press, G. A., & Young-Courchesne, R. (1993). Parietal lobe abnormalities detected with MR in patients with infantile autism. AJR American Journal of Roentgenology, 160, 387–393.

    PubMed  Google Scholar 

  • DeLorey, T. M., Handforth, A., Anagnostaras, S. G., Homanics, G. E., Minassian, B. A., Asatourian, A., et al. (1998). Mice lacking the beta 3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome. The Journal of Neuroscience, 18, 8505–8514.

    PubMed  Google Scholar 

  • DeLorey, T. M., Sahbaie, P., Hashemi, E., Homanics, G. E., & Clark, J. D. (2008). Gabrb3 gene deficient mice exhibit impaired social and exploratory behaviors, deficits in non-selective attention and hypoplasia of cerebellar vermal lobules: A potential model of autism spectrum disorder. Behavioural Brain Research, 187, 207–220. doi:10.1016/j.bbr.2007.09.009.

    Article  PubMed  Google Scholar 

  • Dhossche, D., Applegate, H., Abraham, A., Maertens, P., Bland, L., Bencsath, A., et al. (2002). Elevated plasma gama-aminobutyric acid (GABA) levels in autistic youngsters: Stimulus for GABA hypothesis of autism. Medical Science Monitor, 8, PR1–PR6.

    PubMed  Google Scholar 

  • Fatemi, S. H. (2008). The hyperglutamatergic hypothesis of autism. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 32, 911.

    Google Scholar 

  • Fatemi, S. H., Halt, A. R., Earle, J., Kist, D. A., Realmuto, G. R., Thuras, P. D., et al. (2000). Reduced Purkinje cell size in autistic cerebellum. Biological Psychiatry, 47, S128. doi:10.1016/S0006-3223(00)00687-9.

    Article  Google Scholar 

  • Fatemi, S. H., Halt, A. R., Realmuto, G., Earle, J., Kist, D. A., Thuras, P., et al. (2002b). Purkinje cell size is reduced in cerebellum of patients with autism. Cellular and Molecular Neurobiology, 22, 171–175. doi:10.1023/A:1019861721160.

    Article  PubMed  Google Scholar 

  • Fatemi, S. H., Halt, A., Stary, J., Kanodia, R., Schulz, S. C., & Realmuto, G. (2002a). Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in parietal and cerebellar cortices of autistic subjects. Biological Psychiatry, 52, 805–810. doi:10.1016/S0006-3223(02)01430-0.

    Article  PubMed  Google Scholar 

  • Fatemi, S. H., Stary, J. M., Earle, J. A., Araghi-Niknam, M., & Eagan, E. (2005). GABAergic dysfunction in schizophrenia and mood disorders as reflected by decreased levels of glutamic acid decarboxylase 65 and 67 kDa and Reelin proteins in cerebellum. Schizophrenia Research, 72, 109–122. doi:10.1016/j.schres.2004.02.017.

    Article  PubMed  Google Scholar 

  • Grayson, D. R., Chen, Y., Costa, E., Dong, E., Guidotti, A., Kundakovic, M., et al. (2006). The human Reelin gene: Transcription factors (+), repressors (−) and the methylation switch (+/−) in schizophrenia. Pharmacology & Therapeutics, 111, 272–286. doi:10.1016/j.pharmthera.2005.01.007.

    Article  Google Scholar 

  • Grayson, D. R., Jia, X., Chen, Y., Sharma, R. P., Mitchell, C. P., Guidotti, A., et al. (2005). Reelin promoter hypermethylation in schizophrenia. Proceedings of the National Academy of Sciences of the United States of America, 102, 9341–9346. doi:10.1073/pnas.0503736102.

    Article  PubMed  Google Scholar 

  • Guidotti, A., Auta, J., Davis, J. M., Di-Giorgi-Gerevini, V., Dwivedi, Y., Grayson, D. R., et al. (2000). Decrease in Reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: A postmortem brain study. Archives of General Psychiatry, 57, 1061–1069. doi:10.1001/archpsyc.57.11.1061.

    Article  PubMed  Google Scholar 

  • Guptill, J. T., Booker, A. B., Gibbs, T. T., Kemper, T. L., Bauman, M. L., & Blatt, G. J. (2007). [3H]-flunitrazepam-labeled benzodiazepine binding sites in the hippocampal formation in autism: A multiple concentration autoradiographic study. Journal of Autism and Developmental Disorder, 37, 911–920.

    Google Scholar 

  • Haas, R. H., Townsend, J., Courchesne, E., Lincoln, A. J., Schreibman, L., & Young-Courchesne, R. (1996). Neurologic abnormalities in infantile autism. Journal of Child Neurology, 11, 84–92.

    Article  PubMed  Google Scholar 

  • Hakak, Y., Walker, J. R., Li, C., Wong, W. H., Davis, K. L., Buxbaum, J. D., et al. (2001). Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proceedings of the National Academy of Sciences of the United States of America, 98, 4746–4751. doi:10.1073/pnas.081071198.

    Article  PubMed  Google Scholar 

  • Hogart, A., Nagarajan, R. P., Patzel, K. A., Yasui, D. H., & Lasalle, J. M. (2007). 15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders. Human Molecular Genetics, 16, 691–703. doi:10.1093/hmg/ddm014.

    Article  PubMed  Google Scholar 

  • Homanics, G. E., DeLorey, T. M., Firestone, L. L., Quinlan, J. J., Handforth, A., Harrison, N. L., et al. (1997). Mice devoid of gamma-aminobutyrate type A receptor beta3 subunit have epilepsy, cleft palate, and hypersensitive behavior. Proceedings of the National Academy of Sciences of the United States of America, 94, 4143–4148. doi:10.1073/pnas.94.8.4143.

    Article  PubMed  Google Scholar 

  • Inada, T., Koga, M., Ishiguro, H., Horiuchi, Y., Syu, A., Yoshio, T., et al. (2008). Pathway-based association analysis of genome-wide screening data suggest that genes associated with the gamma-aminobutyric acid receptor signaling pathway are involved in neuroleptic-induced, treatment-resistant tardive dyskinesia. Pharmacogenetics and Genomics, 18, 317–323. doi:10.1097/FPC.0b013e3282f70492.

    Article  PubMed  Google Scholar 

  • Kakinuma, H., Ozaki, M., Sato, H., & Takahashi, H. (2007). Variation in GABA-A subunit gene copy number in an autistic patient with mosaic 4p duplication. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 147B, 973–975.

  • Kim, S. A., Kim, J. H., Park, M., Cho, I. H., & Yoo, H. J. (2006). Association of GABRB3 polymorphisms with autism spectrum disorders in Korean trios. Neuropsychobiology, 54, 160–165. doi:10.1159/000098651.

    Article  PubMed  Google Scholar 

  • Ma, D. Q., Whitehead, P. L., Menold, M. M., Martin, E. R., Ashley-Koch, A. E., Mei, H., et al. (2005). Identification of significant association and gene–gene interaction of GABA receptor subunit genes in autism. American Journal of Human Genetics, 77, 377–388. doi:10.1086/433195.

    Article  PubMed  Google Scholar 

  • McCauley, J. L., Olson, L. M., Delahanty, R., Amin, T., Nurmi, E. L., Organ, E. L., et al. (2004). A linkage disequilibrium map of the 1-Mb 15q12 GABA(A) receptor subunit cluster and association to autism. American Journal of Medical Genetics Part B Neuropsychiatric Genetics, 131, 51–59.

    Google Scholar 

  • Nayate, A., Bradshaw, J. L., & Rinehart, N. J. (2005). Autism and Asperger’s disorder: Are they movement disorders involving the cerebellum and/or basal ganglia? Brain Research Bulletin, 67, 327–334. doi:10.1016/j.brainresbull.2005.07.011.

    Article  PubMed  Google Scholar 

  • Ohnuma, T., Augood, S. J., Arai, H., McKenna, P. J., & Emson, P. C. (1999). Measurement of GABAergic parameters in the prefrontal cortex in schizophrenia: Focus on GABA content, GABA(A) receptor alpha-1 subunit messenger RNA and human GABA transporter-1 (HGAT-1) messenger RNA expression. Neuroscience, 93, 441–448. doi:10.1016/S0306-4522(99)00189-X.

    Article  PubMed  Google Scholar 

  • Palmen, S. J., van Engeland, H., Hof, P. R., & Schmitz, C. (2004). Neuropathological findings in autism. Brain, 127, 2572–2583. doi:10.1093/brain/awh287.

    Article  PubMed  Google Scholar 

  • Persico, A. M., & Bourgeron, T. (2006). Searching for ways out of the autism maze: Genetic, epigenetic and environmental clues. Trends in Neurosciences, 29, 349–358. doi:10.1016/j.tins.2006.05.010.

    Article  PubMed  Google Scholar 

  • Purcell, A. E., Jeon, O. H., Zimmerman, A. W., Blue, M. E., & Pevsner, J. (2001). Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology, 57, 1618–1628.

    PubMed  Google Scholar 

  • Ritvo, E. R., Freeman, B. J., Scheibel, A. B., Duong, T., Robinson, H., Guthrie, D., et al. (1986). Lower Purkinje cell counts in the cerebella of four autistic subjects: Initial findings of the UCLA-NSAC autopsy research repot. The American Journal of Psychiatry, 143, 862–866.

    PubMed  Google Scholar 

  • Saitoh, O., & Courchesne, E. (1998). Magnetic resonance imaging study of the brain in autism. Psychiatry and Clinical Neurosciences, 52, S219–S222. doi:10.1111/j.1440-1819.1998.tb01040.x.

    Article  PubMed  Google Scholar 

  • Samaco, R. C., Hogart, A., & LaSalle, J. M. (2005). Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. Human Molecular Genetics, 14, 483–492. doi:10.1093/hmg/ddi045.

    Article  PubMed  Google Scholar 

  • Schroer, R. J., Phelan, M. C., Michaelis, R. C., Crawford, E. C., Skinner, S. A., Cuccaro, M., et al. (1998). Autism and maternally derived aberrations of chromosome 15q. American Journal of Medical Genetics, 76, 327–336. doi:10.1002/(SICI)1096-8628(19980401)76:4<327::AID-AJMG8>3.0.CO;2-M.

    Article  PubMed  Google Scholar 

  • Steffenburg, S., Gillberg, C., Hellgren, L., Andersson, L., Gillberg, I. C., Jakobsson, G., et al. (1989). A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. Journal of Child Psychology and Psychiatry and Allied Disciplines, 30, 405–416. doi:10.1111/j.1469-7610.1989.tb00254.x.

    Article  Google Scholar 

  • Tochigi, M., Kato, C., Koishi, S., Kawakubo, Y., Yamamoto, K., Matsumoto, H., et al. (2007). No evidence for significant association between GABA receptor genes in chromosome. Journal of Human Genetics, 52, 985–989. doi:10.1007/s10038-007-0207-5.

    Article  PubMed  Google Scholar 

  • Townsend, J., Harris, D. L., & Courchesne, E. (1996). Visual attention abnormalities in autism: Delayed orienting to location. Journal of the International Neuropsychological Society, 2, 541–550.

    Article  PubMed  Google Scholar 

  • Tuchman, R., & Rapin, I. (2002). Epilepsy in autism. Lancet Neurology, 1, 352–358.

    Google Scholar 

  • Yip, J., Soghomonian, J. J., & Blatt, G. J. (2007). Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: Pathophysiological implications. Acta Neuropathologica, 113, 559–568. doi:10.1007/s00401-006-0176-3.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Human tissue was obtained from the NICHD Brain and Tissue Bank for Developmental Disorders; the Harvard Brain Tissue Resource Center, which is supported in part by PHS grant number R24 MH068855; the Brain Endowment Bank, which is funded in part by the National Parkinson Foundation, Inc., Miami, Florida; and the Autism Tissue Program and is gratefully acknowledged. Grant support by Eunice Kennedy Shriver National Institute of Child Health and Human Development (#5R01HD052074-01A2) to SHF is gratefully acknowledged.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to S. Hossein Fatemi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fatemi, S.H., Reutiman, T.J., Folsom, T.D. et al. GABAA Receptor Downregulation in Brains of Subjects with Autism. J Autism Dev Disord 39, 223–230 (2009). https://doi.org/10.1007/s10803-008-0646-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10803-008-0646-7

Keywords

Navigation