Introduction

The anterior cingulate cortex (BA 24; ACC), part of the original Papez circuit of emotion (Papez, 1937), is considered a part of the brain’s limbic lobe and is involved in attention and the regulation of cognitive and emotional processing (Allman et al. 2001; Bush et al. 2000; Heimer and Van Hoesen 2006). Anterior cingulate lesions are known to cause blunted affect, impulsivity, disinhibition, aggressive behavior, disabling obsessions and compulsions, and impaired social judgment including the inability to interpret social clues (Devinsky, 1995).

Neuroanatomical studies have shown that the ACC encompasses a number of specialized subdivisions that subserve a vast array of cognitive, emotional, motor, nociceptive, and visuospatial functions (Bush et al. 2000; Heimer and Van Hoesen 2006; Isomura and Takada 2004; Posner et al., 2007; Zhuo, 2006). The ACC is intimately connected to prefrontal cortex as well as key limbic structures including the hippocampal formation and the amygdala, positioning it as a key structure for roles in executive function, learning and memory and socio-emotional behavior (Pandya et al., 1981; Vogt and Pandya, 1987; Petrides and Pandya, 2007).

In the neurodevelopmental disorder autism, characterized by impairments in communication including language, as well as narrowly focused interests and poor sociability, there is demonstrated neuropathology in the ACC in some reported cases. These were first described by Bauman and Kemper (1985) and recently quantitatively confirmed by Simms et al. (2006), who reported an increased cell packing density and decreased cell size in several subregions within the ACC. Furthermore, positron emission tomography (PET) studies have demonstrated abnormalities in the activation of the ACC in autism during a verbal learning task (Haznedar et al. 1997).

Recent neurochemical research has focused on the gamma-amino-butyric acid (GABA) system and its possible involvement in a number of limbic and cerebellar regions in autistic cases (Blatt et al., 2001; Fatemi et al., 2002; 2009a, b; Guptill et al., 2007; Yip et al., 2007, 2008, 2009). GABA plays a crucial role in normal cortical functioning, information processing, and the formation of brain cytoarchitecture during development (Conti et al., 2004; Di Cristo, 2007; Fritschy et al., 1997; Mohler et al., 1995a). One of the proposed causes of impaired information processing and social behavior in autism is an altered balance between inhibition and excitation in the brain (Rubenstein and Merzenich, 2003). The distribution, electrophysiology, and molecular characteristics of GABA receptors change markedly during development, leaving the formation of the cortex vulnerable to aberrations in neurotransmission at key developmental periods. Seizures are fairly common in individuals with autism, occurring in approximately 25–33% of individuals (Olsson et al., 1988; Volkmar and Nelson, 1990) and may result from abnormal inhibitory control in key cortical areas. Genetic studies have also implicated the GABA system in autism. For example, Schroer et al. (1998) found abnormalities on chromosome 15q11-q13, which includes a cluster of three GABA_A receptor genes (GABRα5, GABRβ3, GABRγ3). Several genetic studies have proposed the involvement of multiple GABA_A receptor subunits and suggest that, through complex interactions, these subunits are involved in autism (Ashley-Koch et al., 2006; Ma et al., 2005).

The GABA_A receptor has binding sites for multiple modulators, including benzodiazepines, making it a target for pharmacological intervention. Benzodiazepines (BZDs) enhance GABA_A receptor mediated neurotransmission, and classically act as sedative/hypnotics to reduce anxiety and suppress seizure activity and panic attacks (Mohler et al., 2000). In clinical studies, BZDs have been reported to elicit paradoxical behavioral responses in some autistic individuals, producing increased anxiety and aggressive behavior (Marrosou et al., 1987). This variable response could be due to an alteration in BZD-sensitive GABA_Areceptors in the specific subset of cases investigated.

Taken together, there is compelling evidence that the GABA system is impacted in autism and alterations in the GABA_A receptor system likely play a role in the etiology of the disorder during development and may contribute to the abnormal phenotype and the variable response to pharmacotherapy. Changes in these key neural substrates in the ACC could disrupt critical circuits involved in socio-emotional behavior as well as other high-order associative functions especially via its abundant prefrontal cortical connectivity. The aim of this study was to determine if the number, density, and distribution of GABA_A receptors and BZD binding sites in the anterior cingulate cortex are altered in postmortem adult autistic cases, and to explore how such alterations might impact individuals with the disorder.Go to: