Downregulation of GABAA Receptor Protein Subunits α6, β2, δ, ε, γ2, θ, and ρ2 in Superior Frontal Cortex of Subjects with Autism

Abstract

We measured protein and mRNA levels for nine gamma-aminobutyric acid A (GABAA) receptor subunits in three brain regions (cerebellum, superior frontal cortex, and parietal cortex) in subjects with autism versus matched controls. We observed changes in mRNA for a number of GABAA and GABAB subunits and overall reduced protein expression for GABAA receptor alpha 6 (GABRα6), GABAA receptor beta 2 (GABRβ2), GABAA receptor delta (GABRδ), GABAA receptor epsilon (GABRε), GABAA receptor gamma 2 (GABRγ2), GABAA receptor theta (GABRθ), and GABAA receptor rho 2 (GABRρ2) in superior frontal cortex from subjects with autism. Our data demonstrate systematic changes in GABAA&B subunit expression in brains of subjects with autism, which may help explain the presence of cognitive abnormalities in subjects with autism.

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

Fig. 1
Fig. 2

References

  1. Abdolmaleky, H. M., Smith, C. L., Zhou, J. R., & Thiagalingam, S. (2009). Epigenetic alterations of the dopaminergic system in major psychiatric disorders. Pharmacogenomics in Drug Discovery and Development Methods in Molecular Biology, 448, 187–212.

    Article  Google Scholar 

  2. Akbarian, S., & Huang, H. S. (2009). Epigenetic regulation in human brain-focus on histone lysine methylation. Biological Psychiatry, 65(3), 198–203.

    PubMed Central  PubMed  Article  Google Scholar 

  3. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (DSM-5) (5th ed.). Washington, DC: American Psychiatric Publishing.

    Google Scholar 

  4. Amiet, C., Gourfinkel-An, I., Bouzamondo, A., Tordjman, S., Baulac, M., Lechat, P., et al. (2008). Epilepsy in autism is associated with intellectual disability and gender: Evidence from a meta-analysis. Biological Psychiatry, 64(7), 577–582.

    PubMed  Article  Google Scholar 

  5. Arias, B., Aguilera, M., Moya, J., Sáiz, P. A., Villa, H., Ibáñez, M. I., et al. (2012). The role of genetic variability in the SLC6A4, BDNF and GABRA6 genes in anxiety-related traits. Acta Psychiatrica Scandinavica, 125(3), 194–202.

    PubMed  Article  Google Scholar 

  6. Banerjee, A., García-Oscos, F., Roychowdhury, S., Galindo, L. C., Hall, S., Kilgard, M. P., et al. (2012). Impairment of cortical GABAergic synaptic transmission in an environmental rat model of autism. International Journal of Neuropsychopharmacology, 11, 1–10.

    Google Scholar 

  7. 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(6), 537–544.

    PubMed  Article  Google Scholar 

  8. Bonnert, T. P., McKernan, R. M., Farrar, S., le Bourdellès, B., Heavens, R. P., Smith, D. W., et al. (1999). Theta, a novel gamma-aminobutyric acid type A receptor subunit. Proceedings of the National Academy of Sciences of the United States of America, 96(17), 9891–9896.

    PubMed Central  PubMed  Article  Google Scholar 

  9. 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. 196–206). Philadelphia, PA: Lippincott, Williams and Wilkins.

    Google Scholar 

  10. Canitano, R. (2013). Novel treatments in autism spectrum disorders: From synaptic dysfunction to experimental therapeutics. Behavioural Brain Research, 251, 125–132.

    PubMed  Article  Google Scholar 

  11. Coghlan, S., Horder, J., Inkster, B., Mendez, M. A., Murphy, D. G., & Nutt, D. J. (2012). GABA system dysfunction in autism and related disorders: From synapse to symptoms. Neuroscience and Biobehavioral Reviews, 36(9), 2044–2055.

    PubMed  Article  Google Scholar 

  12. Cutting, G. R., Curristin, S., Zoghbi, H., O’Hara, B., Seldin, M. F., & Uhl, G. R. (1992). Identification of a putative gamma-aminobutyric acid (GABA) receptor subunit rho2 cDNA and colocalization of the genes encoding rho2 (GABRR2) and rho1 (GABRR1) to human chromosome 6q14-q21 and mouse chromosome 4. Genomics, 12(4), 801–806.

    PubMed  Article  Google Scholar 

  13. D’Hulst, C., De Geest, N., Reeve, S. P., Van Dam, D., De Deyn, P. P., Hassan, B. A., et al. (2006). Decreased expression of the GABAA receptor in fragile X syndrome. Brain Research, 1121(1), 238–245.

    PubMed  Article  Google Scholar 

  14. Dibbens, L. M., Feng, H. J., Richards, M. C., Harkin, L. A., Hodgson, B. L., Scott, D., et al. (2004). GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies. Human Molecular Genetics, 13(13), 1315–1319.

    PubMed  Article  Google Scholar 

  15. El Idrissi, A., Ding, X. H., Scalia, J., Trenkner, E., Brown, W. T., & Dobkin, C. (2005). Decreased GABAA receptor expression in the seizure-prone fragile X mouse. Neuroscience Letters, 377(3), 141–146.

    PubMed  Article  Google Scholar 

  16. Emberger, W., Windpassinger, C., Petek, E., Kroisel, P. M., & Wagner, K. (2000). Assignment of the human GABAA receptor delta-subunit gene (GABRD) to chromosome band 1p36.3 distal to marker NIB1364 by radiation hybrid mapping. Cytogenetics and Cell Genetics, 89(3–4), 281–282.

    PubMed  Article  Google Scholar 

  17. Erickson, C. A., Wink, L. K., Ray, B., Early, M. C., Stiegelmeyer, E., Mathieu-Frasier, L., et al. (2013). Impact of acamprosate on behavior and brain-derived neurotrophic factor: an open-label study in youth with fragile X syndrome. Psychopharmacology, 228(1), 75–84.

    Google Scholar 

  18. Fatemi, S. H., & Folsom, T. D. (2011). Dysregulation of fragile X mental retardation protein and metabotropic glutamate receptor 5 in superior frontal cortex of subjects with autism: A postmortem brain study. Molecular Autism, 2, 6–17.

    PubMed Central  PubMed  Article  Google Scholar 

  19. Fatemi, S. H., Folsom, T. D., Kneeland, R. E., & Liesch, S. B. (2011). Metabotropic glutamate receptor 5 upregulation in children with autism is associated with underexpression of both Fragile X mental retardation protein and GABAA receptor beta 3 in adults with autism. Anatomical Record, 294(10), 1635–1645.

    Article  Google Scholar 

  20. Fatemi, S. H., Folsom, T. D., Reutiman, T. J., & Thuras, P. D. (2009a). Expression of GABA(B) receptors is altered in brains of subjects with autism. Cerebellum, 8(1), 64–69.

    PubMed Central  PubMed  Article  Google Scholar 

  21. Fatemi, S. H., Folsom, T. D., Rooney, R. J., & Thuras, P. D. (2013). mRNA and protein expression for novel GABAA receptors θ and ρ2 are altered in schizophrenia and mood disorders; relevance to FMRP-mGluR5 signaling pathway. Translational Psychiatry, 3, e27.

  22. Fatemi, S. H., Halt, A., Stary, J., Kanodia, R., Schulz, S. C., & Realmuto, G. (2002). Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in parietal and cerebellar cortices of autistic subjects. Biological Psychiatry, 52(8), 805–810.

    PubMed  Article  Google Scholar 

  23. Fatemi, S. H., Reutiman, T. J., Folsom, T. D., Rooney, R. J., Patel, D. H., & Thuras, P. D. (2010). mRNA and protein levels for GABAAalpha4, alpha5, beta1, and GABBR1 receptors are altered in brains from subjects with autism. Journal of Autism and Developmental Disorders, 40(6), 743–750.

    PubMed Central  PubMed  Article  Google Scholar 

  24. Fatemi, S. H., Reutiman, T. J., Folsom, T. D., & Thuras, P. D. (2009b). GABA(A) receptor downregulation in brains of subjects with autism. Journal of Autism and Developmental Disorders, 39(2), 223–230.

    PubMed Central  PubMed  Article  Google Scholar 

  25. Feng, Y., Kapornai, K., Kiss, E., Tamás, Z., Mayer, L., Baji, I., et al. (2010). Association of the GABRD gene and childhood-onset mood disorders. Genes, Brain, and Behavior, 9(6), 668–672.

    PubMed Central  PubMed  Google Scholar 

  26. Fombonne, E. (2006). Past and future perspectives on autism epidemiology. In S. O. Moldin & J. L. R. Rubenstein (Eds.), Understanding autism from basic neuroscience to treatment (pp. 25–48). Boca Raton, FL: CRC/Taylor and Francis.

    Google Scholar 

  27. Gantois, I., Vandescompele, J., Speleman, F., Reyniers, E., D’Hooge, R., Severijnen, L. A., et al. (2006). Expression profiling suggests underexpression of the GABAA receptor subunit delta in the fragile X knockout mouse model. Neurobiology of Disease, 21(2), 346–357.

    PubMed  Article  Google Scholar 

  28. 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 methlyation switch (±) in schizophrenia. Pharmacology and Therapeutics, 111(1), 272–286.

    PubMed  Article  Google Scholar 

  29. Greger, V., Knoll, J. H., Woolf, E., Glatt, K., Tyndale, R. F., DeLorey, T. M., et al. (1995). The gamma-aminobutyric acid receptor gamma 3 subunit gene (GABRG3) is tightly linked to the alpha 5 subunit gene (GABRA5) on human chromosome 15q11-q13 and is transcribed in the same orientation. Genomics, 26(2), 258–264.

    PubMed  Article  Google Scholar 

  30. 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 Disorders, 37(5), 911–920.

    PubMed  Article  Google Scholar 

  31. Gurkan, C. K., & Hagerman, R. J. (2012). Targeted treatments in autism and fragile X syndrome. Research in Autism Spectrum Disorders, 6(4), 1311–1320.

    PubMed Central  PubMed  Article  Google Scholar 

  32. Hagerman, R., Lauterborn, J., Au, J., & Berry-Kravis, E. (2012). Fragile X syndrome and targeted treatment trials. Results and Problems in Cell Differentiation, 54, 297–335.

    PubMed  Article  Google Scholar 

  33. Hatton, D. D., Sideris, J., Skinner, M., Bailey, D. B., Jr, Roberts, J., & Mirrett, P. (2006). Autistic behavior in children with fragile x syndrome: Prevalence, stability, and the impact of FMRP. American Journal of Medical Genetics Part A, 140A(17), 1804–1813.

    PubMed  Article  Google Scholar 

  34. Hernandez, C. C., Gurba, K. N., Hu, N., & Macdonald, R. L. (2012). The GABRA6 mutation, R46W, associated with childhood absence epilepsy, alters 6β22 and 6β2 GABA(A) receptor channel gating and expression. Journal of Physiology, 589(Pt 23), 5857–5878.

    Google Scholar 

  35. Hicks, A. A., Bailey, M. E. S., Riley, B. P., Kamphuis, W., Siciliano, M. J., Johnson, K. J., et al. (1994). Further evidence for clustering of human GABA-A receptor subunit genes: localization of the alpha-6-subunit gene (GABRA6) to distal chromosome 5q by linkage analysis. Genomics, 20, 285–288.

    PubMed  Article  Google Scholar 

  36. 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(6), 691–703.

    PubMed Central  PubMed  Article  Google Scholar 

  37. Hong, A., Zhang, A., Ke, Y., El Idrissi, A., & Shen, C. H. (2012). Downregulation of GABA(A) β subunits is transcriptionally controlled by Fmr1p. Journal of Molecular Neuroscience, 46(2), 272–275.

    PubMed  Article  Google Scholar 

  38. Ito, M., Ohmori, I., Nakahori, T., Ouchida, M., & Ohtsuka, Y. (2011). Mutation screen of GABRA1, GABRB2 and GABRG2 genes in Japanese patients with absence seizures. Neuroscience Letters, 383(3), 220–224.

    Article  Google Scholar 

  39. Jones, K. A., Borowsky, B., Tamm, J. A., Craig, D. A., Durkin, M. M., Dai, M., et al. (1998). GABA(B) receptors function as a heteromeric assembly of the subunits GABA(B)R1 and GABA(B)R2. Nature, 396(6712), 674–679.

    PubMed  Article  Google Scholar 

  40. Kelemenova, S., Schmidtova, E., Ficek, A., Celec, P., Kubranska, A., & Ostatnikova, D. (2010). Polymorphisms of candidate genes in Slovak autistic patients. Psychiatric Genetics, 20(4), 137–139.

    PubMed  Article  Google Scholar 

  41. Khan, Z., Ford, M. J., Cusanovich, D. A., Mitrano, A., Pritchard, J. K., & Gilad, Y. (2013). Primate transcript and protein expression levels evolve under compensatory selection pressures. Science, 342(6162), 1100–1104.

    PubMed Central  PubMed  Article  Google Scholar 

  42. Korpi, E. R., Gründer, G., & Lüddens, H. (2002). Drug interactions at GABA(A) receptors. Progress in Neurobiology, 67(2), 113–159.

    PubMed  Article  Google Scholar 

  43. Kumari, R., Lakhan, R., Kalita, J., Garg, R. K., Misra, U. K., & Mittal, B. (2011). Potential role of GABAA receptor subunit; GABRA6, GABRB2 and GABRR2 gene polymorphisms in epilepsy susceptibility and pharmacotherapy in North Indian population. Clinica Chimica Acta, 412(13–14), 1244–1248.

    Article  Google Scholar 

  44. Laurie, D. J., Seeburg, P. H., & Wisden, W. (1992). The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. II. Olfactory bulb and cerebellum. Journal of Neuroscience, 12(3), 1063–1076.

    PubMed  Google Scholar 

  45. Lenzen, K. P., Heils, A., Lorenz, S., Hempelmann, A., & Sander, T. (2005). Association analysis of the Arg220His variation of the human gene encoding the GABA delta subunit with idiopathic generalized epilepsy. Epilepsy Research, 65(1–2), 53–57.

    PubMed  Article  Google Scholar 

  46. 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(3), 377–388.

    PubMed Central  PubMed  Article  Google Scholar 

  47. Maddox, L. O., Menold, M. M., Bass, M. P., Rogala, A. R., Pericak-Vance, M. A., Vance, J. M., et al. (1999). Autistic disorder and chromosome 15q11-q13: construction and analysis of a BAC/PAC contig. Genomics, 62(3), 325–331.

    PubMed  Article  Google Scholar 

  48. 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, 131B(1), 51–59.

    Article  Google Scholar 

  49. Menold, M. M., Shao, Y., Wolpert, C. M., Donnelly, S. L., Raiford, K. L., Martin, E. R., et al. (2001). Association analysis of chromosome 15 GABAA receptor subunit genes in autistic disorder. Journal of Neurogenetics, 15(3–4), 245–259.

    PubMed  Article  Google Scholar 

  50. Moragues, N., Ciofi, P., Lafon, P., Odessa, M. F., Tramu, G., & Garret, M. (2000). cDNA cloning and expression of a gamma-aminobutyric acid A receptor epsilon-subunit in rat brain. European Journal of Neuroscience, 12(12), 4318–4330.

    PubMed  Google Scholar 

  51. Oblak, A. L., Gibbs, T. T., & Blatt, G. J. (2010). Decreased GABA(B) receptors in the cingulate cortex and fusiform gyrus in autism. Journal of Neurochemistry, 114(5), 1414–1423.

    PubMed Central  PubMed  Google Scholar 

  52. Oblak, A. L., Gibbs, T. T., & Blatt, G. J. (2011). Reduced GABA(A) receptors and benzodiazepine binding sites in the posterior cingulate cortex and fusiform gyrus in autism. Brain Research, 1380, 218–228.

    PubMed Central  PubMed  Article  Google Scholar 

  53. Pham, X., Sun, C., Chen, X., van den Oord, E. J., Neale, M. C., Kendler, K. S., et al. (2009). Association study between GABA receptor genes and anxiety spectrum disorders. Depression and Anxiety, 26(11), 998–1003.

    PubMed Central  PubMed  Article  Google Scholar 

  54. Pirker, S., Schwarzer, C., Czech, T., Baumgartner, C., Pockberger, H., Maier, H., et al. (2003). Increased expression of GABA(A) receptor beta-subunits in the hippocampus of patients with temporal lobe epilepsy. Journal of Neuropathology and Experimental Neurology, 62(8), 820–834.

    PubMed  Google Scholar 

  55. Pirker, S., Schwarzer, C., Wieselthaler, A., Sieghart, W., & Sperk, G. (2000). GABA(A) receptors: Immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience, 101(4), 815–850.

    PubMed  Article  Google Scholar 

  56. Piton, A., Jouan, L., Rochefort, D., Dobrzeniecka, S., Lachapelle, K., Dion, P.A., et al. (2013). Analysis of the effects of rare variants on splicing identifies alterations in GABA(A) receptor genes in autism spectrum disorder individuals. European Journal of Human Genetics (in press).

  57. 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(9), 1618–1628.

    PubMed  Article  Google Scholar 

  58. Represa, A., & Ben-Ari, Y. (2005). Trophic actions of GABA on neuronal development. Trends in Neuroscience, 28(6), 278–283.

    Article  Google Scholar 

  59. Russ, S. A., Larson, K., & Halfon, N. (2012). A national profile of childhood epilepsy and seizure disorder. Pediatrics, 129(2), 256–264.

    PubMed  Article  Google Scholar 

  60. Russek, S. J., & Farb, D. H. (1995). Mapping of the beta 2 subunit gene of the GABAA receptor (GABRB2) to human chromosome 5q34 using fluorescence in situ hybridization. Cellular and Molecular Biological Research, 41(6), 511–513.

    Google Scholar 

  61. Rustan, O. G., Folsom, T. D., Yousefi, M. K., & Fatemi, S. H. (2013). Phosphorylated fragile X mental retardation protein at serine 499, is reduced in cerebellar vermis and superior frontal cortex of subjects with autism: Implications for fragile X mental retardation protein-metabotropic glutamate receptor 5 signaling. Molecular Autism, 4(1), 41.

    PubMed  Article  Google Scholar 

  62. Sasaki, K., Matsuo, M., Maeda, T., Zaitsu, M., & Hamasaki, Y. (2009). Febrile seizures: Characterization of double-stranded RNA-induced gene expression. Pediatric Neurology, 41(2), 114–118.

    PubMed  Article  Google Scholar 

  63. Schwarzer, C., Berresheim, U., Pirker, S., Wieselthaler, A., Fuchs, K., Sieghart, W., et al. (2001). Distribution of the major gamma-aminobutyric acid(A) receptor subunits in the basal ganglia and associated limbic brain areas of the adult rat. Journal of Comparative Neurology, 433(4), 526–549.

    PubMed  Article  Google Scholar 

  64. Sokol, D. K., Maloney, B., Long, J. M., Ray, B., & Lahiri, D. K. (2011). Autism, Alzheimer disease, and fragile X: APP, FMRP, and mGluR5 are molecular links. Neurology, 76(15), 1344–1352.

    PubMed Central  PubMed  Article  Google Scholar 

  65. Surén, P., Roth, C., Bresnahan, M., Haugen, M., Hornig, M., Hirtz, D., et al. (2013). Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. The Journal of the American Medical Association, 309(6), 570–577.

    Article  Google Scholar 

  66. 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 15q11-q13 and autism in a Japanese population. Journal of Human Genetics, 52(12), 985–989.

    PubMed  Article  Google Scholar 

  67. Tucholski, J., Simmons, M. S., Pinner, A. L., Haroutunian, V., McCullumsmith, R. E., & Meador-Woodruff, J. H. (2013). Abnormal N-linked glycosylation of cortical AMPA receptor subunits in schizophrenia. Schizophrenia Research, 146(1–3), 177–183.

    PubMed Central  PubMed  Article  Google Scholar 

  68. Vasquez, K., Kuizon, S., Junaid, M., & Idrissi, A. E. (2013). The effect of folic acid on GABA(A)-B 1 receptor subunit. Advances in Experimental Medicine and Biology, 775, 101–109.

    PubMed  Article  Google Scholar 

  69. Vogel, C. (2013). Protein expression under pressure. Science, 342(6162), 1052–1053.

    PubMed  Article  Google Scholar 

  70. Wang, L. W., Berry-Kravis, E., & Hagerman, R. J. (2010a). Fragile X: leading the way for targeted treatments in autism. Neurotherapeutics, 7(3), 264–274.

    PubMed Central  PubMed  Article  Google Scholar 

  71. Wang, K. S., Liu, X. F., & Aragam, N. (2010b). A genome-wide meta-analysis identifies novel loci associated with schizophrenia and bipolar disorder. Schizophrenia Research, 124(1–3), 192–199.

    PubMed  Article  Google Scholar 

  72. Wilcox, A. S., Warrington, J. A., Gardiner, K., Berger, R., Whiting, P., Altherr, M. R., et al. (1992). Human chromosomal localization of genes encoding the gamma 1 and gamma 2 subunits of the gamma-aminobutyric acid receptor indicates that members of this gene family are often clustered in the genome. Proceedings of the National Academy of Sciences of the United States of America, 89(13), 5857–5861.

    PubMed Central  PubMed  Article  Google Scholar 

  73. Wilke, K., Gaul, R., Klauck, S. M., & Poustka, A. (1997). A gene in human chromosome band Xq28 (GABRE) defines a putative new subunit class of the GABAA neurotransmitter receptor. Genomics, 45(1), 1–10.

    PubMed  Article  Google Scholar 

  74. Wisden, W., Laurie, D. J., Monyer, H., & Seeburg, P. H. (1992). The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon. Journal of Neuroscience, 12(3), 1040–1062.

    PubMed  Google Scholar 

  75. Yip, J., Soghomonian, J. J., & Blatt, G. J. (2007). Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: pathophysiological implications. Acta Neuropathologica, 113(5), 559–568.

    PubMed  Article  Google Scholar 

  76. Yip, J., Soghomonian, J. J., & Blatt, G. J. (2009). Decreased GAD65 mRNA levels in select subpopulations of neurons in the cerebellar dentate nuclei in autism: An in situ hybridization study. Autism Research, 2(1), 50–59.

    PubMed Central  PubMed  Article  Google Scholar 

  77. Yoo, H. K., Chung, S., Hong, J. P., Kim, B. N., & Cho, S. C. (2009). Microsatellite marker in gamma-aminobutyric acid: A receptor beta 3 subunit gene and autism spectrum disorders in Korean trios. Yonsei Medical Journal, 50(2), 304–306.

    PubMed Central  PubMed  Article  Google Scholar 

  78. Zhang, C., Milunsky, J. M., Newton, S., Ko, J., Zhao, G., Maher, T. A., et al. (2009). A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export. Journal of Neuroscience, 29(35), 10843–10854.

    PubMed Central  PubMed  Article  Google Scholar 

  79. Zhao, J., Bao, A. M., Qi, X. R., Kamphuis, W., Luchetti, S., Lou, J. S., et al. (2012). Gene expression of GABA and glutamate pathway markers in the prefrontal cortex of non-suicidal elderly depressed patients. Journal of Affective Disorders, 138(3), 494–502.

    PubMed  Article  Google Scholar 

Download references

Acknowledgments

Human tissue was obtained from the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD) Brain and Tissue Bank for Developmental Disorders, University of Maryland, Baltimore, MD (The role of the NICHD Brain and Tissue Bank is to distribute tissue, and therefore, cannot endorse the studies performed or the interpretation of results); the Harvard Brain Tissue Resource Center, which is supported in part by Public Health Service 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 the Eunice Kennedy Shriver National Institute of Child Health and Human Development (#5R01HD052074-01A2 and 3R01HD052074-03S1) and the Minnesota Medical Foundation Alfred and Ingrid Lenz Harrison Autism Initiative Fund to SHF is gratefully acknowledged. Dr. Fatemi is currently supported by the Bernstein Endowed Professorship in Adult Psychiatry.

Conflict of interest

The authors declare that there is no conflict of interest.

Author information

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. Downregulation of GABAA Receptor Protein Subunits α6, β2, δ, ε, γ2, θ, and ρ2 in Superior Frontal Cortex of Subjects with Autism. J Autism Dev Disord 44, 1833–1845 (2014). https://doi.org/10.1007/s10803-014-2078-x

Download citation

Keywords

  • Autism
  • GABA
  • Brain
  • GABRα6
  • Frontal cortex
  • GABRβ2