Abstract
Autism is a neurodevelopmental disorder that is often comorbid with seizures. Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in brain. GABAB receptors play an important role in maintaining excitatory–inhibitory balance in brain and alterations may lead to seizures. We compared levels of GABAB receptor subunits GABAB receptor 1 (GABBR1) and GABAB receptor 2 (GABBR2) in cerebellum, Brodmann’s area 9 (BA9), and BA40 of subjects with autism and matched controls. Levels of GABBR1 were significantly decreased in BA9, BA40, and cerebellum, while GABBR2 was significantly reduced in the cerebellum. The presence of seizure disorder did not have a significant impact on the observed reductions in GABAB receptor subunit expression. Decreases in GABAB receptor subunits may help explain the presence of seizures that are often comorbid with autism, as well as cognitive difficulties prevalent in autism.
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References
American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, 4th edn. APA, Washington, DC
Fombonne E (2006) Past and future perspectives on autism epidemiology. In: Moldin SO, Rubenstein JLR (eds) Understanding autism from basic neuroscience to treatment. CRC/Taylor and Francis, Boca Raton, pp 25–48
Tuchman R, Rapin I (2002) Epilepsy in autism. Lancet Neurol 1:352–358
Bowery NG (2000) GABAB receptors structure and function. In: Martin DL, Olsen RW (eds) GABA in the nervous system: the view at fifty years. Lippincott, Williams and Wilkins, Philadelphia, pp 233–244
Jones KA, Borowsky B, Tamm JA, Craig DA, Durkin MM, Dai M et al (1998) GABA(B) receptors function as a heteromeric assembly of the subunits GABA(B)R1 and GABA(B)R2. Nature 396:674–679
Kuriyama K, Hirouchi M, Kimura H (2000) Neurochemical and molecular pharmacological aspects of the GABA(B) receptor. Neurochem Res 25:1233–1239
Leung LS, Canning KJ, Shen B (2005) Hippocampal after discharges after GABA(B)-receptor blockade in the freely moving rat. Epilepsia 46:203–216
Li J, Olinger AB, Dassow MS, Abel MS (2003) Up-regulation of GABA(B) receptor mRNA and protein in the hippocampus of cocaine- and lidocaine-kindled rats. Neuroscience 118:451–462
Zai G, King N, Wong GW, Barr CL, Kennedy JL (2005) Possible association between the gamma-aminobutyric acid type B receptor 1 (GABBR1) gene and schizophrenia. Eur Neuropsychopharmacol 15:347–352
Zai G, Arnold P, Burroughs E, Barr CL, Richter MA, Kennedy JL (2005) Evidence for the gamma-amino-butyric acid type B receptor 1 (GABBR1) gene as a susceptibility factor in obsessive–compulsive disorder. Am J Med Genet B Neuropsychiatr Genet 134:25–29
Princivalle AP, Duncan JS, Thom M, Bowery NG (2003) GABA(B1a), GABA(B1b) AND GABA(B2) mRNA variants expression in hippocampus resected from patients with temporal lobe epilepsy. Neuroscience 122:975–984
Tan NC, Heron SE, Scheffer IE, Berkovic SF, Mulley JC (2005) Is variation in the GABA(B) receptor 1 gene associated with temporal lobe epilepsy? Epilepsia 46:778–780
Straessle A, Loup F, Arabadzisz D, Ohning GV, Fritschy JM (2003) Rapid and long-term alterations of hippocampal GABAB receptors in a mouse model of temporal lobe epilepsy. Eur J Neurosci 18:2213–2226
Princivalle AP, Richards DA, Duncan JS, Spreafico R, Bowery NG (2003) Modification of GABA(B1) and GABA(B2) receptor subunits in the somatosensory cerebral cortex and thalamus of rats with absence seizures (GAERS). Epilepsy Res 55:39–51
Han Y, Qin J, Bu DF, Chang XZ, Yang ZX (2006) Successive alterations of hippocampal gamma-aminobutyric acid B receptor subunits in a rat model of febrile seizure. Life Sci 78:2944–2952
Palmen SJ, van Engeland H, Hof PR, Schmitz C (2004) Neuropathological findings in autism. Brain 127:2572–2583
Prosser HM, Gill CH, Hirst WD, Grau E, Robbins M, Calver A et al (2001) Epileptogenesis and enhanced prepulse inhibition in GABA(B1)-deficient mice. Mol Cell Neurosci 17:1059–1070
Schuler V, Lüscher C, Blanchet C, Klix N, Sansig G, Klebs K et al (2001) Epilepsy, hyperalgesia, impaired memory, and loss of pre- and postsynaptic GABA(B) responses in mice lacking GABA(B(1)). Neuron 31:47–58
Canitano R (2007) Epilepsy in autism spectrum disorders. Eur Child Adolesc Psychiatry 16:61–66
Binnie CD (1993) Significance and management of transitory cognitive impairment due to subclinical EEG discharges in children. Brain Dev 15:23–30
Fatemi SH, Halt A, Stary J, Kanodia R, Schulz SC, Realmuto G (2002) Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in parietal and cerebellar cortices of autistic subjects. Biol Psychiatry 52:805–810
Yip J, Soghomonian JJ, Blatt GJ (2007) Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: pathophysiological implications. Acta Neuropathol 113:559–568
Fatemi SH, Reutiman TJ, Folsom TD, Thuras PD (2008) GABA(A) receptor down regulation in brains of subjects with autism. J Autism Dev Disord (in press)
Acknowledgements
Human tissue was obtained from the NICHD Brain and Tissue Bank for Developmental Disorders (University of Maryland); TARF; 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, FL, USA; and the Autism Tissue Program and is gratefully acknowledged. Grant support by National Institute of Child Health and Human Development (#5R01HD052074-01A2) to SHF is gratefully acknowledged.
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Fatemi, S.H., Folsom, T.D., Reutiman, T.J. et al. Expression of GABAB Receptors Is Altered in Brains of Subjects with Autism. Cerebellum 8, 64–69 (2009). https://doi.org/10.1007/s12311-008-0075-3
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DOI: https://doi.org/10.1007/s12311-008-0075-3