Alterations in Key GABAergic Biomarkers in Autism: Potential Disruption of Inhibitory Networks

Although autism is a heterogeneous disorder ranging from mild to severe in nature, changes in the GABAergic system is emerging as a consistent neuropathological finding in affected brain areas. An ideal brain region to study these changes is the cerebellum, whose intrinsic GABAergic circuitry forms the foundation of its output to thalamic and cerebral cortical areas. Specifically, in the posterior lateral cerebellar cortex (Crus II region), the density/number of GABA receptors (GABAAR, GABABR and benzodiazepine binding sites) is altered in adult autism subjects. Furthermore changes in GAD 65 or 67 mRNA have been found in inhibitory neurons in the cerebellar cortex and, in a subpopulation of neurons in the dentate nucleus. These neurons are thought to project back to the inferior olivary complex exerting inhibitory control of its electrotonic coupling of excitatory climbing fiber (CF) responses. Immunohistochemical labeling has shown abnormal accumulation of neurofilaments in some CFs on PC dendrites potentially altering transmitter release. Thus a number of key GABAergic biomarkers have emerged suggesting a cascade of events with strong implications to disrupt olivocerebellar circuitry in adult autism subjects. An interesting development is that some of these biomarkers demonstrate similar alterations across other affected brain areas including the hippocampus, anterior and posterior cingulate cortex (BA 24, 23) and fusiform gyrus (BA 37). This suggests widespread effects of altered inhibitory circuits throughout affected regions in autism.