Alterations in GABAergic biomarkers in the autism brain: research findings and clinical implications

Abstract

Autism is a pervasive developmental disorder characterized by repetitive stereotyped behavior, social-emotional deficits, and delayed or absent language abilities. There are known neuropathologies in the autism brain affecting limbic, cerebellar, and cortical structures but the neurochemical profile of affected individuals, revealed in postmortem tissue studies, is only recently emerging. One major component that appears highly impacted in autism is the GABAergic system. It is now apparent that there are widespread significant effects in many distributed regions in the autism brain revealed by histochemical, autoradiographic, and biochemical studies. The key synthesizing enzymes for GABA, glutamic acid decarboxylase type 65 and 67 (GAD65 and GAD67), are decreased in the cerebellum and closer examination of mRNA levels revealed that it is largely due to decreases in Purkinje cells and a subpopulation of larger dentate neurons as measured by in situ hybridization studies. Other cell types had either normal GAD levels (Golgi cells, smaller dentate interneurons, and stellate cells) or increased levels (basket cells). GABA receptor density, number, and protein expression are all decreased in the cerebellum and in select cortical areas. GABA(A) and GABA(B) subunit protein expression was significantly reduced in cerebellum, BA 9 and BA 40. Benzodiazepine binding sites were significantly reduced in the hippocampus and anterior cingulate cortex (BA 24). Taken together, data from these studies suggest that there is a marked dysregulation of the inhibitory GABA system in the autism brain affecting particular biomarkers localized to specific cell types and lamina likely influencing circuitry and behavior.

Figure 1

³[H]flunitrazepam labeled BZD binding sites in the anterior cingulate cortex in a control case compared to an individual with autism. The binding density has been pseudocolored to show differences in binding in the superficial and deep layers. The red label indicates high binding and the yellow label represents lower binding. In the study of 7 adult autism cases and 9 control cases there was a 28.9% reduction in benzodiazepine binding sites in the autism cases in the superficial layers (red labeled region) and a 16.4% decrease in the deep cortical layers (yellow labeled region) compared to controls (Oblak et al., 2009).

Figure 2

Representative samples of GABRα1 (51 kDa), GABRα2 (51 kDa), GABRα3 (55 kDa), GABRβ3 (56 kDa), GABBR1 (108 kDa), GABBR2 (105 kDa), and β-Actin (42 kDa) in BA9, BA40, and cerebellum of subjects with autism (A) and matched controls (C). Note: Images for GABRα1, GABRα2, GABRα3, and GABRβ3 are reprinted with kind permission from Springer Science+Business Media: Journal of Autism and Developmental Disorders, GABA_A Receptor Downregulation in Brains of Subjects with Autism, volume 39, 2009, page 226, Fatemi SH, Reutiman TJ, Folsom TD, Thuras PD, Figure 1. Images for GABBR1, GABBR2, and β-Actin protein levels are reprinted with kind permission from Springer Science+Business Media: Cerebellum, Expression of GABA(B) Receptors Is Altered in Brains of Subjects with Autism, volume 8, 2009, page 67, Fatemi SH, Folsom TD, Reutiman TJ, Thuras PD, Figure 1.