Gene expression patterns that underlie functional brain activity in healthy individuals are disrupted in autism

By Azra Jaferi, Ph.D.

Recent rapid advances in both human brain imaging and genomics have revealed that human brain activity is influenced by gene activity (Fakhoury, Prog. Neuropsychopharmacol. Biol. Psychiatry, 2018; Hashem et al., Transl. Psychiatry, 2020). A recent study combined brain imaging and postmortem approaches to understand how the gene activity that typically underlies functional brain activity in neurotypical individuals is affected in autism spectrum disorder (ASD) (Berto et al., Nat. Commun., 2022).

PVALB and SCN1B spatial distribution. A comparison between the genes correlated with rs-fMRI in individuals without ASD in the current study and genes correlated with rs-fMRI measurements in previous studies revealed an overlap of six genes. Of these, two genes, SCN1B and PVALB, also showed differential correlations between individuals with and without ASD, suggesting a role of these genes in regulating brain circuits affected in ASD. Both genes have a rostro-caudal pattern of expression, with higher expression in the occipital regions. Image adapted from Berto S. et al. Nature Commun. 13, 3328.

The new study, led by Genevieve Konopka, examined gene expression (RNA sequencing) in 11 brain regions from a large number of donors with an ASD diagnosis and a group of typically developing individuals for comparison. Postmortem brain tissue was partly obtained from Autism BrainNet. In the same brain regions where they measured gene expression, the researchers obtained measures of brain activity for participants with ASD and those who are typically developing from a large functional magnetic resonance imaging (fMRI) dataset, which is part of the Autism Brain Imaging Data Exchange.

The researchers first identified gene activity in 11 brain regions that correlate with the fMRI measurements. Next, they discovered that this correlation between gene expression and functional brain activity is altered in the brains of individuals with ASD. Changes were found, especially in a subset of genes that are important for brain development, including SCN1B and PVALB. This finding suggested that gene expression patterns that typically support functional brain activity in neurotypical individuals might be altered in ASD.

Given that ASD is a neurodevelopmental condition, the researchers next wanted to find out how the relationship between gene activity and brain activity compared between the individuals with and without autism across development. They found that the genes that show altered relationships with brain activity in people with ASD follow a different developmental trajectory suggesting their role in brain development.

In taking a closer look at these gene groups across development, the researchers also found that in ASD, the genes highly expressed in early development were found in excitatory neurons, whereas the genes highly expressed in adulthood were found in inhibitory (parvalbumin) interneurons that regulate brain excitatory/inhibitory balance which is thought to be disrupted in ASD (Ferguson and Gao, Front. Neural Circuits, 2018).

In summary, Konopka and colleagues showed an atypical relationship between gene expression and functional brain activity in individuals with ASD. They provide key insights into developmental expression patterns of ASD-related genes important for brain excitation/inhibition balance and the cortical regions having the greatest impact of gene expression on brain activity in ASD. The findings from this study move us one step closer to understanding alterations of brain activity in individuals with ASD.