Autism spectrum disorder (ASD) is a neurodevelopmental disorder that broadly impacts perceptual, cognitive, social and motor functions. Across individuals, the disorder manifests with a large degree of phenotypic diversity. Hence, understanding the various combined dysfunctions in individuals afflicted with ASD represents a considerable challenge. While a few syndromic and high-confidence risk genes manifest directly in ASD, the large majority of candidate genes are likely to be of small effect. The question, therefore, arises as to how one translates our present understanding of the genetics of ASD into a mechanistic understanding of how this disorder affects brain development and function.

In recent years, multiple studies have identified a convergence of possible mechanisms implicated in the etiology of autism. The emergence of transcriptomic profiling at single-cell resolution has provided for the first time the means to determine the precise cellular expression of ASD candidate genes during vulnerable developmental periods.

ASD originates within the late embryonic and early postnatal period and developmental defects in GABAergic and cholinergic neurons have been implicated as potential causal factors. To explore the neurodevelopmental etiology of ASD, Gordon Fishell and Jordane Dimidschstein’s laboratories propose to combine human genetic data with large-scale transcriptomic and epigenetic analyses to examine the genetic origins of GABAergic and cholinergic populations. Specifically, the researchers aim to assess how developmental expression of the diverse set of genes implicated in ASD may help identify biological processes occurring within these specific neuronal populations during the early steps of fate specification. Complementing this approach, they also propose to develop viral tools to target and manipulate these cell populations. Findings from these studies will help to identify key biological processes affected by ASD risk genes. Such knowledge may also help to identify ASD biomarkers as well as advancing the development of earlier diagnostics and targeted therapeutic approaches.