Autism spectrum disorder (ASD) is characterized by changes in sensory perception, integration of information across different senses and simple forms of sensory learning. To better understand the changes in the brain that cause these symptoms, Ethan Scott plans to look at activity in thousands of brain cells simultaneously in transparent zebrafish as they respond to sensory inputs. The huge datasets from these experiments will reveal how sensory information normally flows through the brain and how this flow changes in zebrafish with mutations in ASD risk genes.

Jun Huh will examine human-derived bacteria that can colonize the guts of pregnant mice to identify bacteria that can promote anti-inflammatory responses. Such factors could help to prevent the development of brain pathologies and behavioral phenotypes relevant to autism in offspring that can be triggered by uncontrolled inflammatory activity during pregnancy.

De novo mutations contribute to a large fraction of autism spectrum disorders (ASD) risk, but the contribution of complex variant types remains largely unexplored. Melissa Gymrek aims to utilize her recently developed novel computational tools to evaluate the role of genetic variation in repetitive regions of the genome in ASD.

Genomic and transcriptomic studies implicate fetal cerebral cortex transcriptional dysregulation in ASD, but the implicated regulatory elements, their target genes and their role in development remain unclear. Flora Vaccarino will use cortical organoids derived from individuals with ASD to investigate whether transcriptional dysregulation of specific cell types during early development represents a convergent pathophysiology in ASD.

John Huguenard has preliminary data to suggest that neuronal axons don't develop normally in two mouse models of ASD that result from maternal immune activation. In the current proposal, Huguenard will test if this is a common feature across ASD mouse models, by assessing axonal structure and function in four additional environmental and genetic models.

Angelman syndrome is a severe neurodevelopmental disorder caused by deletion or mutation of the maternal allele of UBE3A. Mark Zylka plans to utilize CRISPR/Cas9 technology to activate the dormant but functional paternal Ube3a in a mouse model of Angelman syndrome and assess long-term effects on behavior. This preclinical gene therapeutic approach has the potential to advance a first-in-class treatment for an autism spectrum disorder.

Tbr1 is a high-confidence ASD risk gene that plays a crucial role in neocortical synaptic development. John Rubenstein plans to examine the molecular mechanisms by which Tbr1 regulates synaptogenesis in order to understand how alterations to Tbr1 contribute to ASD pathophysiology.

Len Pennacchio will utilize his laboratory’s expertise in high-throughput enhancer screening to experimentally test whether noncoding autism-associated sequence variants alter the function of transcriptional enhancers that normally drive gene expression in the developing brain.

Helen Tager-Flusberg previously developed a standardized protocol for assessing expressive language outcomes in school- and home-based settings in children with autism that produces results comparable to assessments made in a lab or clinic setting. Tager-Flusberg now seeks to apply the success of that work in older children by developing a version of their protocol that can be used by parents to assess language ability in younger children at home.

Jonathan Mill’s project aims to characterize multiple layers of gene regulation during brain development, facilitating a systematic exploration of hypotheses related to the neurodevelopmental origins of autism. Further, by characterizing genetic effects on gene regulation during neurodevelopment, this work will facilitate the interpretation of genetic findings for autism.