Many people on the autism spectrum have difficulty processing everyday sensory information. In the current project, Edmund Lalor aims to explore the underlying causes of this difficulty by analyzing brain responses to predictable and unpredictable speech in adolescents with and without autism. In doing so, the project also aims to produce clinically useful measures of sensation, perception and language function in people with autism.

Shinjae Chung and Ted Abel will assess the neural dynamics of sleep neurons in Syngap1 mutant mice, aiming to understand how changes in their activity lead to sleep disturbances and behaviors associated with autism.

William Moody plans to test the hypothesis that disruptions in neonatal sleep-wake cycles, which are known to occur in autism spectrum disorder, cause abnormalities in early electrical activity which, in turn, result in neurodevelopmental changes associated with this condition.

Recent breakthroughs in antisense oligonucleotide (ASO) therapy have demonstrated that the damaging effects of some disease-causing mutations can be corrected in vivo. However, ASD susceptibility genes that are implicated by de novo mutations consist predominantly of dominant ‘haploinsufficiencies,’ for which ASO therapeutics have not yet been developed. Jonathan Sebat aims to demonstrate an approach to antisense therapy that is effective for boosting the expression level of specific ASD genes.

Haploinsufficiency describes a case in which one of two copies of a gene is mutated and the remaining copy is insufficient to maintain normal function; this mechanism is likely acting in many cases of de novo mutations occurring in autism spectrum disorder (ASD). In the current project, Daniel Geschwind’s team aims to utilize enhancer-targeting gene activation methods to correct the effect of these mutations; stem cell–derived cortical spheroids will be used to comprehensively visualize the development of neuronal subtypes at the cellular and molecular level. This study will enhance our understanding of how haploinsufficiency in ASD genes impacts neuronal development and provide a proof-of-principle for gene activation as a therapeutic intervention.

Identifying the distinct biological mechanisms at play in autism spectrum disorder (ASD) may help to better understand the heterogeneous manifestations of this complex condition. Jessica Ann Lasky-Su and Rachel Kelly contend that utilizing the metabolome as a composite measure of both genetic and environmental influences in a biofluid such as plasma will identify distinct subgroups groups of ASD individuals with common underlying biological mechanisms. Findings from this project may lead to the development of metabo-endotype approaches to optimize treatment.

The discovery of rare genetic variants in individuals with autism spectrum disorders (ASD) has led to the identification of nearly 100 high-confidence ASD risk genes. What is currently missing is clear convergent pathways linking the proteins encoded by these genes at the molecular level. In this project, Paul Jenkins’ team plans to study the interaction of two proteins encoded by the ASD risk genes ANK2 and SCN2A to understand how they work together to control neuronal signaling during development.

The abundance of mutations in chromatin regulatory proteins in ASDs highlights the significance of chromatin structure in brain development. Kavitha Sarma and colleagues plan to study whether RNA-containing chromatin structures called R-loops are molecular drivers of deregulated gene expression in ASDs. They will also test the possibility of targeting R-loops for future therapy in ASDs.

How autism-associated genes are differentially spliced during brain development remains largely unknown. Xiaochang Zhang aims to combine single cell RNA-seq with long-read sequencing to investigate cell-type-specific mRNA isoforms that are expressed during neocortical development. He plans to apply this knowledge to the interpretation of mutations associated with autism risk, leading to a better understanding of how gene expression and development may be affected in autism.

Humans and other animals display a strong evolutionary conserved motivation to engage in social interactions. Changes in social interactions have been observed in individuals with ASD as well as animal models of the condition. In the current project, Catherine Dulac’s laboratory aims to uncover the nature and function of neural circuits underlying social motivation in wildtype mice compared to those observed in two distinct genetic mouse models of ASD.