Mutations in 51 RNA-binding proteins have been strongly implicated in autism spectrum disorder (ASD). Howard Lipshitz aims to develop experimental resources for the study of these proteins in neuronal development, provide genome-wide information on the dynamics of mRNA regulation during neuronal differentiation and identify the target RNAs of eight high-priority ASD-associated RNA-binding proteins, thus predicting the molecular functions of these proteins.

The transcripts of most high-confidence ASD risk genes bind to the translational regulatory RNA-binding protein CPEB4. In the current project, John Flanagan and colleagues plan to study the function of CPEB4 in mouse cortical development and downstream mRNAs that are regulated by this protein. Findings from these studies are expected to identify principles that link together ASD risk genes and unifying cellular mechanisms that underly ASD pathogenesis.

Impulsivity, the inability to suppress inappropriate behaviors, is a hallmark of executive control and a feature of autism spectrum disorder (ASD). Adam Kepecs’ project aims to establish a new model system to study behavioral inhibition, one that combines neurofibromatosis-1 mouse models with a quantitative cross-species behavioral paradigm to understand the role of dopamine in impulsivity.

Deficits in feedforward inhibition mediated by parvalbumin-expressing (PV+) cortical interneurons are common among animal models of autism. In the current project, Oscar Marín and Beatriz Rico plan to investigate molecular mechanisms regulating the formation of excitatory synapses onto PV+ interneurons. Specifically, they will focus their studies on the ErbB4-Tsc2-mTOR signaling pathway. Findings from these studies will provide insights into the development of an important pool of synaptic connections of relevance for autism.

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.