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.

Fragile X syndrome, an autism spectrum disorder and the most common genetic form of intellectual disability in males, is caused by the loss of function of FMRP. In the current project, Gene Yeo plans to investigate whether reduction of a protein antagonist of FMRP can rescue disease-relevant deficits in human stem cell and mouse models of fragile X syndrome.

Autism spectrum disorder (ASD) is a complex condition associated with many different molecular and genetic causes. In the current project, Tim Buschman and colleagues aim to test the hypothesis that these different underlying causes of ASD converge to disrupt the flow of neural activity through the brain. They plan to do this by studying three different mouse models of ASD. Understanding these common disruptions and relating changes in neural activity to behavioral phenotypes will lay the foundation for improving biomarkers and treatments for ASD.

Analyzing when, how, and in which cell types autism spectrum disorder (ASD) pathology arises within the human brain will require a genetically tractable model system that can mimic human embryonic and fetal brain development. In the current project, Jürgen Knoblich’s team plans to combine 3-D tissue culture, CRISPR-based perturbations and single-cell RNA sequencing technology to study transcriptomic alterations in response to loss-of-function mutations in high-risk ASD genes. By characterizing perturbation-induced transcriptomic changes across dozens of cell types in the developing human cortex, they hope to uncover common and unique molecular pathways that bridge genetic mutations to ASD phenotypes.

Chronic gastrointestinal issues, including pain and constipation, are common among individuals with autism spectrum disorder (ASD), yet the mechanisms through which gastrointestinal dysfunction occur in ASD are not understood. The current project aims to investigate the development and function of peripheral sensory neurons that regulate gastrointestinal function in mice and determine whether this neuronal population is dysfunctional in genetic mouse models of ASD.