Autism Spectrum Disorder

Study: Molecular Changes in Autism Span Cerebral Cortex

Differences in transcript and gene expression can further our understanding of autism spectrum disorder, as well as genetic risk factors identified in the following study.

November 16, 2022

The brains of autistic individuals experience widespread molecular changes across the cerebral cortex. The most differential changes occur in the primary visual cortex, according to a recent study published in Nature that analyzed 11 cortical areas of the brain.1 Most molecular profiling studies highlight changes limited to the frontal and temporal cortex.

To further understand the brain pathology of autism spectrum disorder (ASD), researchers performed RNA-sequencing analysis on 112 post-mortem samples. Consistent transcriptomic signatures of ASD were found across all cortical regions analyzed in the study. The greatest signal of expression came from the primary visual cortex (BA17).

When compared to control samples, ASD brains demonstrated significantly reduced gene expression between regions of the cerebral cortex. The primary visual cortex and parietal cortex (BA39/40), which function as primary sensory regions, exhibited significant patterns of attenuation. These results suggest cortical regions are more molecularly homogeneous in autistic individuals and pronounced in the posterior region of the brain.

“It is interesting to speculate that the substantial changes observed in primary sensory regions may relate to the widespread sensory processing differences in ASD, which are so pervasive that they have been included in the DSM-5 diagnostic criteria,” the researchers wrote.

An attenuation of transcriptomic regional identity (ARI) translates to a “reduction in the magnitude of gene expression” and was often used as a marker in the current study. By grouping ARI up- and down-regulated genes into co-expression modules, researchers identified consistent dysregulation that spanned cortical association regions in ASD samples. Neuronal changes (GeneM9), astrocyte reactivity (GeneM32), and blood-brain barrier disruption (GeneM24) were found to extend beyond the frontotemporal regions. ASD genetic risk variants (GeneM5 and IsoformM37) were also identified.

“The findings presented here substantially refine our understanding of ASD molecular pathology beyond the previously established ‘downregulated neuron’ and ‘upregulated glia/immune’ functional categories observed in frontal and temporal lobes.”

Of the 112 post-mortem samples, 49 were individuals with idiopathic ASD and 54 were matched neurotypical controls. A total of 725 brain samples were used. An ASD diagnosis was confirmed using the Autism Diagnostic Interview–Revised or based on clinical history. Samples were collected through the Harvard Brain Bank as part of the Autism Network Project, in addition to the University of Maryland Brain Banks.

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1Gandal, M.J., Haney, J.R., Wamsley, B. et al. Broad transcriptomic dysregulation occurs across the cerebral cortex in ASD. Nature (2022).