Decreased GABA(A) 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: 4.33). 08/2009; 2(4):205-19. DOI: 10.1002/aur.88
Source: PubMed


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.

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    • "According to post-mortem studies, subjects with ASD display a paucity of GABAergic Purkinje cells in the cerebellum (Ritvo et al. 1986; Bauman and Kemper 2005), an increased cell packing density of GABAergic interneurons in the hippocampus (Lawrence et al. 2010), small neuron size in the hippocampal pyramidal cell laminae and a decrease of neurons in the lateral amygdala and fusiform gyrus (Amaral et al. 2008; van Kooten et al. 2008). Additionally, a reduction of GABA A (Blatt et al. 2001; Guptill et al. 2007; Fatemi et al. 2009a; Oblak et al. 2009; Fatemi et al. 2014) and GABA B (Fatemi et al. 2009b; Fatemi et al. 2010) receptor levels have been reported in several brain tissue regions (i.e. hippocampus, superior frontal cortex) of individuals with ASD. "
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