A postmortem brain study pinpoints specific cell types in the temporal cortex where gene expression is altered in autism – revealing changes in neuronal communication and neuroinflammation

By Azra Jaferi, Ph.D.

Synopsis
A postmortem brain study uncovered autism-related changes in gene expression in specific neurons of the superior temporal gyrus (STG) — an area of the temporal cortex implicated in autism, language processing, and social perception.

Introduction
Over the last decade, research using postmortem brain tissue has revealed changes in gene expression in the brains of individuals with autism spectrum disorder (ASD) compared to those without ASD1,2. Most of these previous studies have examined brain tissue in bulk, which contains a large mixture of different types of cells. Although analysis of bulk tissue has uncovered valuable information about gene expression changes in ASD, the changes specific to certain cell types could be masked when measurements are made across numerous cell types as a whole. Pinpointing the specific cell types in which gene expression is altered in ASD allows for a more fine-tuned approach to characterizing ASD and finding particular targets in the brain for potential treatments. This level of cell-specific resolution was undertaken in a recent postmortem brain study3 led by Cynthia Schumann at the University of California, Davis, Michael Gandal at the University of Pennsylvania, and Boryana Stamova at the University of California, Davis. The study looked at gene expression in both bulk tissue and individual cells from postmortem brains of individuals with or without ASD, with a focus on an area of the temporal cortex — the superior temporal gyrus (STG) — previously implicated in ASD and thought to influence language processing and social perception4,5.

Methodology
Schumann and her colleagues investigated gene-expression changes in the STG by using RNA sequencing analysis, a genomic tool that allows researchers to find changes in the complete set of RNA sequences in cells (known as the transcriptome). This provides insights about which genes are turned on or off in a cell and helps identify molecular pathways that might be altered in ASD. They performed RNA sequencing of bulk STG tissue from 59 postmortem brains, acquired in part from Autism BrainNet. Of these 59 brains, almost half (27) were from individuals with ASD and the rest (32) were from individuals without ASD, ranging in age from 2 to 73 years. To obtain more cell-specific information, the researchers performed a method known as laser capture microdissection to isolate specific brain cells (neurons) from STG sections of the same postmortem brains profiled using RNA sequencing in bulk tissue.

Findings and implications for autism
The results showed several important differences in the STG of postmortem brains from individuals with ASD compared to those without ASD. In bulk STG tissue from individuals with ASD, there was over-representation of proteins involved in the stress response and immune system (specifically, heat-shock proteins)6,7. Adding to these bulk-tissue findings, the researchers’ analysis of STG neurons from individuals with ASD revealed significantly increased expression of regulatory factors and genes related to immune responses, including excessive activation of the immune response in the brain (a process known as neuroinflammation). In further analysis, in which the researchers applied a modeling approach to their data from STG neurons, a direct link was shown between inflammation and ASD in neurons. These findings show that cell stress and neuroinflammation may be signature changes of STG neurons in individuals with ASD.

In addition to neuroinflammation, the study’s findings also pointed to significantly altered neuronal activity. The analysis in bulk STG tissue showed decreased expression of genes related to the functioning of synapses (the sites where communication between neurons occurs), as well as changes in genes involved in the production of GABA, the primary inhibitory neurotransmitter in the brain. The expression of these genes (GAD1 and GAD2) was also overall reduced in STG neurons. These findings provide support, at a cellular level, to the idea of an imbalance of excitatory-to-inhibitory activity in the brains of individuals with ASD8 which is one of the major hypotheses of the biological basis of ASD9.

Interestingly, the GABA-related changes in ASD became more profound with age — decreases in GAD1 and GAD2 genes in ASD were found mainly in the postmortem brains of individuals in late adulthood. These age-related findings support the premise that brain development in individuals with ASD, including development of GABA-related inhibitory activity, takes a different direction from the neurotypical trajectory beginning in childhood and continues to evolve across the lifespan10.

Schumann and her colleagues’ analysis at the level of neurons, alongside their analysis of bulk tissue, allowed for a more detailed picture of alterations in the STG in individuals with ASD. The collective findings of altered neuronal communication, neuroinflammation, and age-related gene expression changes in the STG help pinpoint pathways and genes directly linked to ASD, and lead to a better understanding of the development of ASD over the human lifespan.

References

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