SFARI

Research into the developmental underpinnings of autism spectrum disorder (ASD) is hampered by a lack of techniques for describing neural development at the cellular and circuit levels. Ethan Scott and his colleagues plan to use zebrafish as a platform for anatomical and functional analyses of ASD etiology at the level of individual neurons and the circuits that they form. Zebrafish larvae are transparent, allowing neural development in the intact animal to be examined with a range of microscopic and optogenetic techniques.

In autism, tracing the connections between the underlying genes, altered brain function and behavioral symptoms is difficult because the disorder is caused by multiple factors in most people. Richard Tsien and Ricardo Dolmetsch of Stanford University in Palo Alto, California, Randall Rasmusson of the State University of New York at Buffalo and their colleagues study a form of the disorder linked to a single mutation, which may provide insights into the other forms of autism caused by many factors.

Single-nucleotide polymorphism genotyping and whole-exome and whole-genome sequencing studies have been key for the identification of genetic loci and mutations underlying autism spectrum disorder (ASD) susceptibility. Although none of the risk genes identified so far contribute to more than 1 percent of ASD cases, overall the search for ASD treatments can profoundly benefit from the study of rare and syndromic forms of ASDs.

Genetics plays a central role in autism spectrum disorder (ASD), yet much remains unknown about how DNA sequence variation predisposes individuals to ASD. Rare mutations have emerged as critical in ASD, and there is great hope that whole-genome sequencing will reveal many more causal mutations and lead to a better understanding of genetics and pathogenesis in ASD. This presumes that we will be able to identify which DNA mutations predispose individuals to ASD against the background of the millions of benign or unrelated DNA mutations present in every human genome. For mutations that disrupt proteins, such causal relationships have been successfully demonstrated, leading to significant new insights into the etiology of ASD. However, the majority of the human genome does not code for proteins, and predicting which mutations are pathogenic in noncoding regions is much more challenging. Enhancers — regulatory DNA sequences within our genomes that control when genes are activated — have emerged as critically important to human health and development. It is likely that noncoding mutations that disrupt enhancers also contribute to the pathogenesis of ASD.

Social situations are processed and responded to differently in ASD. Here, Bence Ölveczky and Naoshige Uchida plan to use the rat as a model for social interactions and to parse possible mechanisms underlying these differences.

Benjamin Blencowe aims to systematically elucidate the molecular and genetic mechanisms associated with the (mis)regulation and function of a neuronal microexon network frequently disrupted in autism. The methods and datasets generated by the project are expected to provide a framework for future investigations of RNA regulatory networks disrupted in autism as well as in other nervous system disorders and diseases.

Atypical perceptual integration, in which sensory information is combined over time, is widely observed in individuals with ASD. In this project, Benjamin Scott aims to use online computer games to measure meaningful differences in perceptual integration across a range of children and adolescents with and without ASD. This approach will enable rigorous, quantitative assessment of perception across the population and will provide important insights into cognitive mechanisms that underly ASD.

In this project, Bence Ölveczky aims to garner insight into the neural circuit-level changes associated with autism and how these lead to motor-related manifestations of the condition. To this end, the project will combine long-term continuous neural recordings in the striatum with quantitative measurements of behavior in freely behaving rats.

Research assessing the effectiveness of treatments in autism spectrum disorder (ASD) is limited by a lack of scalable and quantifiable autism-specific treatment response measures. Assessing treatment success would be benefited by the development of response measures that can be administered ‘blindly’ and are sensitive enough to capture change over short periods of time, flexible enough to be used across studies and are standardized in order to be comparable across sites.