Autism spectrum disorder (ASD) is a multifactorial spectrum of neurodevelopmental conditions with complex genetic traits underlying their etiology. To hypothesize whether genes implicated in ASD affect the development or function of specific brain circuits, researchers often intersect ASD risk gene lists with transcriptomic data sets of the human cerebral cortex across development.

Previous reports and preliminary single-cell RNA sequencing (scRNAseq) data on the prenatal brain indicate that several ASD risk genes show enriched expression in neurons of the subplate, a transient zone underneath the cortical plate that is evolutionarily expanded in primates and plays a critical role in the development of the cortex. Remarkably, some of these genes express in a regional manner across the cortex, implicating spatially distinct subtypes of subplate neurons in ASD. However, there is a lack of high-quality validation of such spatiotemporal expression patterns of ASD genes in subplate neurons and other neural types in intact human brain tissue.

In the current project, Omer Bayraktar’s research team, in collaboration with Tomasz Nowakowski, plans to validate the spatiotemporal expression pattern of ASD risk genes in subplate neurons in the developing and adult human brain using high-throughput spatial transcriptomics. Specifically, the teams will initiate the development of a spatio-temporal autism gene expression (STAGE) resource, consisting of data from intact human brain tissue surveyed using a new transcriptome-wide in situ hybridization method based on NanoString’s Whole Transcriptome Atlas (WTA) technology¹. This approach will be used to validate ASD risk gene expression in regional populations of human subplate neurons in situ across two disease-related cortical areas in the developing and adult human cerebral cortex.

These experiments will help confirm if regional subtypes of human subplate neurons are implicated in ASD. In future experiments, STAGE can be expanded to assay all human cortical areas across the life-span. These efforts will lead to a comprehensive cellular map of ASD gene expression and illuminate the cellular origins of ASD.