Article

Decreased GABAA receptors and benzodiazepine binding sites in the anterior cingulate cortex in autism.

Boston University School of Medicine, Anatomy and Neurobiology, Boston, Massachusetts 02118, USA.
Autism Research (Impact Factor: 4.53). 08/2009; 2(4):205-19. DOI: 10.1002/aur.88
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
101 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: T-Brain-1 (TBR1), a causative gene in autism spectrum disorders (ASDs), encodes a brain-specific T-box transcription factor. It is therefore possible that TBR1 controls the expression of other autism risk factors. The downstream genes of TBR1 have been identified using microarray and promoter analyses. In this study, we annotated individual genes downstream of TBR1 and investigated any associations with ASDs through extensive literature searches. Of 124 TBR1 target genes, 23 were reported to be associated with ASDs. In addition, one gene, Kiaa0319, is a known causative gene for dyslexia, a disorder frequently associated with autism. A change in expression level in 10 of these 24 genes has been previously confirmed. We further validated the alteration of RNA expression levels of Kiaa0319, Baiap2, and Gad1 in Tbr1 deficient mice. Among these 24 genes, four transcription factors Auts2, Nfia, Nr4a2, and Sox5 were found, suggesting that TBR1 controls a transcriptional cascade relevant to autism pathogenesis. A further five of the 24 genes (Cd44, Cdh8, Cntn6, Gpc6, and Ntng1) encode membrane proteins that regulate cell adhesion and axonal outgrowth. These genes likely contribute to the role of TBR1 in regulation of neuronal migration and axonal extension. Besides, decreases in Grin2b expression and increases in Gad1 expression imply that neuronal activity may be aberrant in Tbr1 deficient mice. These analyses provide direction for future experiments to reveal the pathogenic mechanism of autism. Autism Res 2015. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.
    Autism Research 01/2015; · 4.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by impaired social interaction and communication, and restricted behavior and interests. A disruption in the balance of excitatory and inhibitory neurotransmission has been hypothesized to underlie these disorders. Here we demonstrate that genes of both pathways are affected by ASD, and that gene expression of inhibitory and excitatory genes is altered in the cerebral cortex of adult but not younger autistic individuals. We have developed a measure for the difference in the level of excitation and inhibition based on gene expression and observe that in this measure inhibition is decreased relative to excitation in adult ASD compared to control. This difference was undetectable in young autistic brains. Given that many psychiatric features of autism are already present at an early age, this suggests that the observed imbalance in gene expression is an aging phenomenon in ASD rather than its underlying cause.
    Frontiers in neuroscience. 01/2014; 8:394.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent studies have found that hundreds of genetic variants, including common and rare variants, rare and de novo mutations, and common polymorphisms contribute to the occurrence of autism spectrum disorders (ASDs). The mutations in a number of genes such as neurexin, neuroligin, postsynaptic density protein 95, SH3, and multiple ankyrin repeat domains 3 (SHANK3), synapsin, gephyrin, cadherin, and protocadherin, thousand-and-one-amino acid 2 kinase, and contactin, have been shown to play important roles in the development and function of synapses. In addition, synaptic receptors, such as gamma-aminobutyric acid receptors and glutamate receptors, have also been associated with ASDs. This review will primarily focus on the defects of synaptic proteins and receptors associated with ASDs and their roles in the pathogenesis of ASDs via synaptic pathways.
    Frontiers in Cellular Neuroscience 09/2014; 8:276. · 4.18 Impact Factor

Full-text (2 Sources)

Download
37 Downloads
Available from
May 17, 2014