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.

The major goal of the pilot study is to unravel the neural correlates underlying disturbances in rapid eye movement (REM) sleep in a mouse model of 16p11.2 deletion syndrome. Weber’s teams will test whether reduced activity in the prefrontal cortex contributes to the suppression of phasic REM sleep, resulting in fewer rapid eye movements. Additionally, they will explore whether restoring phasic REM sleep can alleviate memory impairments observed in these mice.

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.

Multiple studies, including genetics, have implicated mitochondrial dysfunction among the many factors affecting the risk of developing autism-related symptoms. However, it has been challenging to link polygenic influencers of autism spectrum disorder (ASD) risk from population studies to relative mitochondrial energetic weakness in individuals. This study attempts to use previous large-scale genetic studies of ASD to create a mitochondrial polygenic function score, then to apply this score to the Simons Simplex Collection. LCLs from individuals at either end of the genetic mitoPFS spectrum will then be assayed for their mitochondrial energetic function. A validated mitoPFS, and blood-based assay for mitochondrial energetics itself, would be an invaluable tool for identifying ASD individuals for clinical trials involving mitochondrial therapeutics.