Decreased GABAA receptors and benzodiazepine binding sites in the anterior cingulate cortex in autism.
The anterior cingulate cortex (ACC; BA 24) via its extensive limbic and high order association cortical connectivity to prefrontal cortex is a key part of an important circuitry participating in executive function, affect, and socio-emotional behavior. Multiple lines of evidence, including genetic and imaging studies, suggest that the ACC and gamma-amino-butyric acid (GABA) system may be affected in autism. The benzodiazepine binding site on the GABA(A) receptor complex is an important target for pharmacotherapy and has important clinical implications. The present multiple-concentration ligand-binding study utilized (3)H-muscimol and (3)H-flunitrazepam to determine the number (B(max)), binding affinity (K(d)), and distribution of GABA(A) receptors and benzodiazepine binding sites, respectively, in the ACC in adult autistic and control cases. Compared to controls, the autistic group had significant decreases in the mean density of GABA(A) receptors in the supragranular (46.8%) and infragranular (20.2%) layers of the ACC and in the density of benzodiazepine binding sites in the supragranular (28.9%) and infragranular (16.4%) lamina [corrected]. These findings suggest that in the autistic group this downregulation of both benzodiazepine sites and GABA(A) receptors in the ACC may be the result of increased GABA innervation and/or release disturbing the delicate excitation/inhibition balance of principal neurons as well as their output to key limbic cortical targets. Such disturbances likely underlie the core alterations in socio-emotional behaviors in autism.
Oblak
A
A
Boston University School of Medicine, Anatomy and Neurobiology, Boston, Massachusetts 02118, USA. aoblak@bu.edu
Gibbs
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Blatt
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GJ
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D001321:Autistic Disorder / Q000235:genetics* / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D005445:Flunitrazepam / Q000493:pharmacokinetics; D006179:Gyrus Cinguli / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009118:Muscimol / Q000493:pharmacokinetics; D011963:Receptors, GABA-A / Q000235:genetics*; D012016:Reference Values; D055815:Young Adult
D048868:Adaptor Proteins, Signal Transducing; D011963:Receptors, GABA-A; C117357:TSPOAP1 protein, human; D009118:Muscimol; D005445:Flunitrazepam