The UBE3A gene, encoding the ubiquitin ligase UBE3A/E6AP, is a high-confidence risk gene for autism spectrum disorder (ASD) but the downstream targets of UBE3A-mediated ubiquitination are poorly defined. In the current project, Hiroaki Kiyokawa plans to apply a novel proteomic technique called ‘orthogonal ubiquitin transfer’ to identify neuronal-specific substrates of UBE3A. Successful completion of this project is expected to provide a novel high-resolution perspective about neuronal-specific pathways downstream of UBE3A and identify potential therapeutic targets for ASD.

More than half of the genes associated with autism spectrum disorders (ASDs) encode for regulatory proteins. In the current project, Kasper Lage’s team aims to unravel the regulatory networks of transcription factors TCF4, CHD8, DYRK1A and GIGYF1 in human induced pluripotent stem cell (iPSC)-derived glutamatergic excitatory neurons using newly developed genome-wide chromatin-binding profiling methods. They then plan to use integrative computational methods to associate the identified regulatory networks with ASD genome-wide association studies and exome sequencing data to identify the subnetworks and sets of target genes most enriched in ASDs.

Gastrointestinal (GI) distress commonly accompanies autism spectrum disorders (ASDs), significantly impacting the quality of life of those affected and their families. Julia Dallman, in collaboration with John Rawls, plans to use zebrafish as an experimental system, since it allows for the GI tract to be imaged and manipulated in live animals. They aim to determine if GI phenotypes in multiple genetic forms of ASD are caused by convergent gut-intrinsic mechanisms. The expected outcomes would open a new field of GI research for ASD that could suggest treatment strategies for managing GI distress in humans.

Neurexins constitute a family of presynaptic transmembrane molecules that are encoded by three distinct genes, and mutations in all three genes are associated with risk for autism spectrum. In mammals, neurexins are expressed as thousands of different splice isoforms, all containing an invariant intracellular domain responsible for an as yet uncharacterized downstream signaling pathway. In the current project, Peri Kurshan and colleagues plan to use the simpler in vivo system afforded by the nematode C. elegans, along with a recently developed proteomics approach, to identify the proteins responsible for neurexin’s downstream signaling pathway(s).

Understanding how ASD risk genes alter the course of cortical circuit development is necessary to advance targeted therapies. In the current project, Jason Wester plans to investigate how Arid1b mutations in different types of neurons within the mouse cerebral cortex leads to pathological circuit configurations that disrupt information processing.

Enrico Domenici and colleagues aim to take advantage of the availability of whole-genome sequencing data from salivary DNA of participants in SPARK to verify the hypothesis of an altered microbiome in ASD. This proposal will extend the genetic characterization of the SPARK cohort beyond the host genome, building a framework for a systems biology view of the brain-microbiome axis in ASD.

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.