White Matter Glial Pathology in the Cingulate Cortex of Autism Spectrum Disorder Subjects

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Autism spectrum disorder (ASD) is considered a disease of neuronal dysfunction based on pathological alterations in axon thickness and neuronal disorganization. Recent findings suggest non-neuronal cells may also play a role in ASD brain pathology. White matter areas in the ASD brain display enlargement paired with a reduction in structural integrity. These structural abnormalities are likely associated with dysfunction of the most prevalent cell types present in white matter, astrocytes and oligodendrocytes. In fact, myelin abnormalities and structural changes of reactive astrocytes have been reported in ASD. The goal of the present study was to further investigate glia pathology in the white matter of the ASD brain. The primary brain area of interest was the anterior cingulate cortex (BA24) because this brain region mediates social interactive behavior, disruption of which is a core behavioral feature of ASD. Furthermore, a reduction in the structural integrity of white matter in BA24 has been observed in ASD. Postmortem brain tissues were obtained from highly characterized ASD and developmentally normal control donors. Quantitative Western blotting was used to measure glial fibrillary acidic protein (GFAP) and myelin oligodendrocyte glycoprotein (MOG) produced by astrocytes and oligodendrocytes, respectively. A significant elevation in levels of GFAP-immunoreactivity (p=0.005) in BA24 white matter was observed in ASD as compared to control donors. In contrast, levels of MOG-immunoreactivity in BA24 white matter were similar when comparing ASD to control donors. Levels of both GFAP and MOG in the BA24 gray matter from the same subjects were similar comparing the two groups of donors. Measurement of GFAP gene expression in BA24 white matter did not reveal any difference between ASD and control donors. To further examine the regional specificity of the observed glial pathology, we analyzed GFAP and MOG protein expression in the anterior prefrontal cortex (BA10) white matter. Levels of GFAP- and MOG-immunoreactivities were unchanged in BA10 white matter comparing ASD to control donors. These findings demonstrate that astrocytic pathology is both tissue-specific (white matter) and regionally selective (BA24) in ASD. Elevation of GFAP protein in BA24 white matter implies an activation of astrocytes possibly as a result of a yet undefined cellular insult. Research is needed to investigate the molecular pathways that underlie this astrocyte reaction and such research may yield important clues regarding the etiology of ASD.

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