To advance our understanding of the epigenetic contribution to autism, Zhaolan (Joe) Zhou aims to test a hypothesis that the transcription of broad enhancer-like chromatin domain (BELD) genes is particularly sensitive to mutations in chromatin genes and that deregulation of those BELD genes underlies the pathogenesis of autism. The ultimate goal is to provide a foundation to identify possible points of biological convergence and promote mechanism-based therapeutic development.

One of the overall goals of autism research is to discover convergent mechanisms underlying the condition across individuals. With this goal in mind, Eirene Markenscoff-Papadimitriou aims to look for common mechanisms of dysfunction that result from mutations in two autism risk genes, POGZ and ADNP. Knock-out mouse models, as well as stem-cell derived neurons lacking these two genes, will be studied to assess what impact the loss of these two genes has on cortical gene expression and chromatin state.

Brain imaging in children and adults with autism spectrum disorder (ASD) have identified excessive local connectivity and long-range dysconnectivity in the cerebral cortex. In this project, Kartik Pattabiraman aims to use single cell-level transcriptomic and viral circuit tracing approaches to spatiotemporally characterize mouse cortical subplate neurons and characterize their role in cortical circuit assembly and disruption associated with ASD.

The SFARI gene database lists both GIGYF1 and GIGYF2 as high confidence risk factors, as both have a probability of loss of function intolerance (pLI) score of 1. It is our hypothesis that GIGYF1/2 mutations disrupt the function of the GIGYF1/2-4EHP translation repression, thus resulting in dysregulation of protein synthesis which causes impaired synaptic function and susceptibility to behavioral impairments. We will use cell-specific GIGYF1/2 conditional knockout mice, which will be subjected to a battery of behavioral tests, ribosome profiling and proteomics to investigate the mice for behavioral impairments and changes in translational efficiency. Our goal is to provide novel insight into the molecular mechanisms mediating ASD-like behaviors via GIGYF1/2 and establish a preclinical basis for therapeutic intervention in ASD patients.

The tremendous genotypic and phenotypic diversity in ASD has made it extremely challenging to pinpoint causal mechanisms, distinguish the effects of individual genetic variants, stratify patients into subtypes and develop treatments. In the current project, Randall J. Platt plans to profile patient-specific CHD8 variants in human-derived stem cells and induced neurons. The overall aim is to functionally dissect CHD8 mutations and help prioritize convergent/divergent mechanisms for future studies.

This project is developing and applying new spatial transcriptomic methods to simultaneously probe neuroanatomy and gene expression in the brains of mouse autism models providing an integrated, high-resolution picture of the impact that autism-associated genetic mutations have on gene regulation, cellular make-up of the brain and brain wiring.

Dysregulated levels of neuromodulators and other chemical signals may contribute to behavioral characteristics of ASD. Yet previous efforts have often focused on only one signal at a time, and typically provide a static description of signal levels in the brain. In the current project, Mark Andermann and colleagues plan to use novel optical methods to track and control dozens of neuromodulators and peptides in the brain of a genetic mouse model of ASD.

Infection or inflammation during critical windows of pregnancy, termed “maternal immune activation” (MIA), has been strongly associated with increased risk of neurodevelopmental and neuropsychiatric conditions in children, including autism spectrum disorder. In the current project, Brian Kalish and Yeong Shin Yim aim to discover how MIA elicits a sex-specific effect on RNA metabolism and to target these pathways to reduce MIA-associated behavioral alterations in mice.