Our project is a proof-of-concept study to determine differences in the phosphorylation status of proteins in different striatal cell types in a novel mouse model of the Okur-Chung neurodevelopmental syndrome that is driven by a mutation in the kinase CK2. The aim is to ascertain if master signal transduction pathways can be identified that are differentially regulated in specific neuron types, which is of crucial importance when developing novel therapeutical approaches for ASD.

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.

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.