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.

Genetic studies have identified a large number of genes that increase the risk for autism. Many of these risk genes function to regulate the genome in the developing brain. Anne West aims to identify common regulatory mechanisms used by many ASD risk genes that may explain convergent effects on gene regulation during neurodevelopment.

In this pilot study, Pierre Vanderhaeghen and his team aim to explore the intricate connections between ASD, mitochondrial function, and human neuronal development, with a specific focus on developmental timing. Innovative tools, including an in vitro model for studying mitochondrial morphology, dynamics, and function and an in vivo xenotransplantation model of human cortical neurons, will be used to achieve this. The investigation seeks to understand how mitochondrial dynamics and metabolism contribute to the pathology of ASD-linked mutations in genes such as MECP2 and SYNGAP1.

In this project, Joris de Wit and colleagues plan to assess the role of ASD risk genes in the development of a specific thalamocortical circuit, connecting the posterior medial nucleus (POm) of the thalamus and intratelencephalic layer 5 pyramidal neurons (IT L5 PNs) in the cortex. This circuit is of particular interest due to its potential link to sensory processing, a function often found to be altered in autistic individuals.

Marta Biagioli and colleagues intend to provide further proof of the efficacy of RNA therapy, proposing SINEUP technology as a new RNA-based tool for the treatment of genetic ASDs. Her lab intends to share validated SINEUP reagents with the ASD community so that SINEUP therapeutic properties could be further analyzed to streamline the development of these molecules to the clinic.