Autism can be caused by dysregulated gene expression during development. In the current project, Reza Kalhor plans to create in vivo longitudinal recordings of target gene expression as the mouse brain develops in a series of increasingly complex differentiation and patterning events. Gene expression changes in neurotypical and mouse models of autism will be compared to aid in our understanding of how the foundation for autism phenotype is laid during embryogenesis.

Excessive activity of UBE3A, an E3 ubiquitin ligase, is linked to a prevalent form of autism. The current proposal will analyze genetic variants in UBE3A to develop peptide inhibitors that can inhibit its enzymatic activity.

Matthew MacDonald, Bernie Devlin and Kathryn Roeder plan to leverage the most recent genomic results and integrate them with a wealth of high-quality proteome and transcriptome data to achieve a deeper understanding of how different classes of genetic susceptibility and different ASD risk genes converge on overlapping biological networks critical to ASD.

The overall goal of Xin Tang’s project is to yield insights into the molecular programs that lead to reduced KCC2 gene expression in neurons from individuals with autism and to consequently develop mechanism-guided drugs that restore KCC2 gene expression and ultimately reverse symptoms of the condition.

Defining how epigenetic modification of chromatin regulates neural stem cell proliferation is relevant to understanding the brain overgrowth exhibited by a proportion of people with ASD. Here, Michael Piper’s goal is to understand how the epigenetic landscape regulates transcriptional activity during brain development and how abnormalities in this process can lead to brain overgrowth and ASD.

Altered proportions of cortical excitatory and inhibitory neurons have been postulated to occur in individuals with ASD. In the current project, Flora Vaccarino and colleagues plan to use a lineage barcoding system in human organoids to decipher whether precursor cells from ASD individuals perform different lineage choices than those from neurotypical individuals. Such findings will help to decipher whether excitatory/inhibitory neuronal imbalance is due to a true lineage imbalance (i.e., where certain progenitors are intrinsically programmed to make different fate choices) as opposed to an imbalance variably dictated by cell-extrinsic, microenvironmental cues.

Hundreds of human genes involved in dozens of different molecular and cellular mechanisms are associated with an increased risk of autism, though it is unclear how these disparate genetic factors all seem to lead to the same core set of characteristics. In the current project, Michael F. Wells aims to discover points of biological convergence across nearly a dozen high-confidence autism risk genes through human-derived stem cell-based screens. Findings from these studies could improve drug discovery efforts by identifying dysfunctional gene networks and cellular phenotypes that are shared across different genetic risk profiles.

In the current project, Mirjana Maletić-Savatić plans to examine the metabolic status and integrity of different types of cells in brain organoids derived from individuals with 16p11.2 copy number variants (CNVs). The comprehensive data resulting from this project are expected to provide mechanistic insights into new therapeutic targets for 16p11.2 CNV conditions.

Sleep disruption is a common comorbidity in people with ASD, but the potential role that sleep disruption plays in the etiology of ASD has not been clear. Recent studies have demonstrated that early life sleep disruption could cause long-lasting changes in behavior in genetically vulnerable ASD model mice. Here, Graham Diering and colleagues plan to use biochemistry and proteomics methods to test the idea that the developing synapse is a node of vulnerability to the effects of sleep disruption relevant for ASD.