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.

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.

A key challenge in individuals with ASD is decision-making in social contexts. To address this gap, Herbert Wu and colleagues plan to apply circuit and systems tools to a novel paradigm in mice to study how ASD risk genes impact social decision-making. This project aims to break new ground for tackling the impairment in social behaviors associated with ASD, offering insights into potential interventions and treatments.

In the current project, Zeynep Coban Akdemir plans to improve the classification of protein truncating variants, which account for a significant proportion of pathogenic variants. The goal is to enhance predictive models and tools to classify these variants by utilizing multi-omics approaches and functional characterizations. The overall aim is to increase the accuracy of diagnosing ASD in individuals undergoing genome-wide sequencing and ultimately lead to the development of new targeted therapies.

While oral texture aversion and concomitant feeding issues are a significant and persistent problem for many autistic individuals, the mechanisms underlying oral texture sensitivity disruptions in ASD are not understood. Here, Lauren Orefice aims to identify the cellular and circuit-level mechanisms of dysfunction underlying oral texture hypersensitivity in mouse models for ASD, which may lead to a novel therapeutic target for texture-based feeding issues.

The ability to recognize others’ moods, emotions and intentions from facial expressions is altered in autistic individuals compared to neurotypical individuals. Kohitij Kar and colleagues plan to investigate neural circuit mechanisms that underlie such atypical behavior in autistic adults by developing a nonhuman primate (rhesus macaque) model of ASD-relevant facial emotion processing.