Understanding how mutations in autism risk genes impact brain development is critical to identifying the root causes of the condition. In the current project, Anthony Koleske aims to determine how variants in the autism risk gene Trio impact brain development and function in mice.

Social dysfunction is one of the salient features of autism spectrum disorder (ASD). In preliminary results, Peter Walter and colleagues have found that a small-molecule integrated stress response (ISR) inhibitor, ISRIB, restores social deficits observed in a mouse model of traumatic brain injury. In the current project, they plan to explore whether ISRIB also corrects changes in social, repetitive and communicative behaviors in a variety of different mouse models of ASD in order to assess its potential value as an ASD treatment strategy.

Challenges in social behaviors make up some of the most salient features of autism spectrum disorder (ASD), yet effective treatments to improve social behaviors remain elusive. To address this need, Mauro Costa-Mattioli aims to expand upon the promise of a microbial-based therapy (i.e., treatment with Lactobacillus reuteri) to improve social behaviors in rodent models of ASD by better defining its scope of effectiveness and precise mechanisms of action. Findings from this study will help to better inform future translational studies and could advance the development of microbial-based therapeutics for ASD.

Edward Chang aims to address auditory and speech processing in individuals with epilepsy and autism, with the specific goal of understanding how auditory, phonological and linguistic representations are affected. Understanding how these well-characterized neural representations of speech-relevant acoustic features are impacted in individuals with autism at the level of specific populations of neurons will provide mechanistic insight that may lead to behavioral, pharmacological and neuromodulatory therapies that act in much more targeted ways than is currently possible.

The sensory and neural mechanisms that mediate social communication facilitating attachment and how they are affected in the context of autism spectrum disorder (ASD) are poorly understood. Prairie voles are small rodents that display long-term relationships between peers and mates. Devanand Manoli proposes to understand how specific mutations in two ASD risk genes, Shank3 and Scn2a, disrupt the processing of social cues, leading to the identification of brain regions that could inform targeted interventions to improve social communication in ASD.

Motor development is an early behavioral domain that shows significant heritability and may have links with the development of autism. In the current project, Angelica Ronald and Mark Johnson seek to investigate these links further through initial gene discovery work on early motor development followed by state-of-the-art analyses testing for overlap in the common genetic architecture between motor development and autism.

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.