SYNGAP1 encodes a neuronal Ras GTPase activating protein and is a significant risk gene associated with autism spectrum disorders (ASDs) and intellectual disability (ID). As many of the genetic mutations in individuals with SYNGAP1-related ID (SRID) lead to decreased SYNGAP1 expression, SRID is an ideal candidate for genetic and antisense oligonucleotide–based therapies that increase SYNGAP1 expression. Leveraging recently discovered regulatory mechanisms of SYNGAP1 expression, Richard Huganir’s team plans to design precision antisense oligonucleotides that increase SYNGAP1 expression and to validate them using human pluripotent stem cell models of SRID. These studies will help to advance the therapeutic potential of antisense oligonucleotide–based treatments for SRID as well as other monogenic forms of ID and ASD.

In the current project, Corey Harwell and colleagues plan to examine the impact of loss of Setd2 function on the proliferation and cell fate specification of cortical progenitors. Their studies of the cellular and molecular functions of Setd2 during cortical neurogenesis may provide insights into convergent molecular mechanisms by which other chromatin-associated autism risk genes contribute to autism pathogenesis.

Motor imitation of other people’s movements is critical for social-communicative skill development and is affected in individuals with autism spectrum disorder (ASD). In the current project, Steward Mostofsky and colleagues plan to advance the validity and scalability of a computerized “videogame-like” assessment of motor imitation that they have successfully developed and piloted to distinguish ASD in children with a high degree of accuracy. Their goal is to move from using 3-D Kinect system cameras to using low-cost, off-the-shelf 2-D cameras, thereby enabling widespread use of this assessment method in clinics and home settings.

Autism spectrum disorders are often characterized by challenges in learning socially transmitted behaviors like social skills and language. In the current project, Todd Roberts’s team aims to establish a research program to test how the most significant ASD risk genes impact neural circuits involved in socially oriented learning and in the sensorimotor imitation of observed vocal behaviors in songbirds. FoxP1 will be studied as a first exemplar, since it is a high-risk ASD gene that is associated with significant speech and language impairments.

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.