Individuals with autism spectrum disorder (ASD) have changes in brain activity, as measured by brain imaging techniques (Hashem et al., Transl. Psychiatry, 2020). They also display changes in gene expression patterns in specific brain regions and cell types (Velmeshev et al., Science, 2019). Recent rapid advances in both human brain imaging and genomics have been able to reveal that human brain activity is influenced by gene expression patterns (Fakhoury, Prog. Neuropsychopharmacol. Biol. Psychiatry, 2018; Hashem et al., Transl. Psychiatry, 2020). Combining these two approaches helps bridge the gap between the large number of gene variants now linked to ASD risk (SFARI Gene) and their biological effects on the brain, and ultimately on behavior. In a recent study supported in part by a SFARI Research Award, SFARI Investigator Genevieve Konopka and colleagues coupled brain imaging with measures of gene expression to reveal how gene expression patterns in the cortex that typically underlie functional brain activity in neurotypical individuals are disrupted in ASD (Berto et al., Nat. Commun., 2022). In their coupling of two diverse measurements, the investigators uncover ASD-related mechanisms that may be missed when using only one type of dataset.
The study examined gene expression (RNA sequencing) in 11 cortical regions of postmortem brain tissue from a large number of brain donors with an ASD diagnosis and a group of typically developing individuals. Postmortem brain tissue was partly obtained from Autism BrainNet, a program of SFARI. In the same cortical regions where they measured gene expression, the researchers obtained measures of brain activity from a large functional magnetic resonance imaging (fMRI) dataset from the Autism Brain Imaging Data Exchange (ABIDE I and II), which contains participants with ASD and those who are typically developing. To strengthen their findings, the researchers used two independent resting-state fMRI measurements — known as fractional amplitude of low-frequency fluctuations (fALFF) and regional homogeneity (ReHo) — which can assess both brain activity and connectivity.
In the first step of the study, the researchers identified genes with expression patterns in the 11 cortical 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, especially for a subset of genes important for brain development, including SCN1B and PVALB. This finding suggested that the brain gene expression patterns that typically support functional brain activity in neurotypical individuals might be affected in ASD.
The differentially correlated genes in individuals with ASD versus typically developing individuals were identified across all ages included in the study (5 to 64 years old). However, given that ASD is a neurodevelopmental condition, the researchers next wanted to find out how these genes compare between the two groups across development. They found that genes that differently correlate with brain activity in people with ASD compared to neurotypical individuals follow a specific developmental trajectory in individuals with ASD compared with people without ASD. This was reflected by three main clusters of these genes, with one cluster being highly expressed in adults, another highly expressed in early development, and a third cluster having a relatively stable trajectory throughout development. Interestingly, genes in the adult cluster were upregulated until adulthood in typically developing individuals, but this typical pattern of upregulation was delayed in individuals with ASD.
In taking a closer look at these gene clusters in relation to specific cell types, the researchers found that, in ASD, the gene cluster highly expressed in early development was overrepresented in excitatory neurons, while the adult gene cluster was overrepresented in inhibitory interneurons expressing parvalbumin, a regulator of brain excitatory/inhibitory balance thought to be disrupted in ASD (Ferguson and Gao, Front. Neural Circuits, 2018). Further, the highest enrichment of adult and early-development cluster genes was in cortical regions associated with vision and proprioception, reinforcing the emerging role of the visual cortex in the development of ASD.
In conclusion, Konopka and colleagues showed an atypical relationship between gene expression and functional brain activity in individuals with ASD, with changes in the visual cortex being a major contributor to the differences in this gene-activity relationship. 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 brain activity in individuals with ASD.