Identification of genetic contributions to autism risk has the potential to greatly improve the efficacy of diagnostic methods and treatment approaches. In the current project, Charles Langley and Gary Karpen plan to take advantage of recent improvements in human genome sequencing and analysis to determine if variation in the size or composition of previously inaccessible regions enriched for repeated DNAs impact autism risk.

Autism is a neurodevelopmental condition with a strong genetic basis, but a gap in knowledge exists between genetic and behavioral phenotypes due to a lack of neurophysiological explanation. To bridge the gap, Hiroki Asari aims to characterize and rescue changes in visual processing in autism model mice using causal experimental tools in modern systems neuroscience.

De novo, recurrent mutations in a regulatory subunit of protein phosphatase 2A (PPP2R5D, a high-confidence ASD risk gene) result in Jordan’s syndrome. Stefan Strack and colleagues have generated novel mouse models that recapitulate cardinal features of this syndrome. The current project aims to define molecular signatures and evaluate potential treatments of the disorder.

Mutations in chromatin modifiers are frequently observed in individuals with ASD. In the current project, Matthias Stadtfeld and colleagues aim to understand how loss of EHMT1 – a high-confidence ASD risk gene that encodes a histone methyltransferase – perturbs molecular and cellular functions during human neurogenesis.  They also plan to evaluate the therapeutic potential of restoring physiological levels of this enzyme.

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.