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.

This project is developing and applying new spatial transcriptomic methods to simultaneously probe neuroanatomy and gene expression in the brains of mouse autism models providing an integrated, high-resolution picture of the impact that autism-associated genetic mutations have on gene regulation, cellular make-up of the brain and brain wiring.

Dysregulated levels of neuromodulators and other chemical signals may contribute to behavioral characteristics of ASD. Yet previous efforts have often focused on only one signal at a time, and typically provide a static description of signal levels in the brain. In the current project, Mark Andermann and colleagues plan to use novel optical methods to track and control dozens of neuromodulators and peptides in the brain of a genetic mouse model of ASD.

Infection or inflammation during critical windows of pregnancy, termed “maternal immune activation” (MIA), has been strongly associated with increased risk of neurodevelopmental and neuropsychiatric conditions in children, including autism spectrum disorder. In the current project, Brian Kalish and Yeong Shin Yim aim to discover how MIA elicits a sex-specific effect on RNA metabolism and to target these pathways to reduce MIA-associated behavioral alterations in mice.

Cognitive control deficits are one of the frequent challenges accompanying ASD. However, very little is known about the link between ASD risk genes and neural circuit mechanisms in control of cognitive control behavior. In the current project, Hirofumi Morishita plans to use mouse models to test the hypothesis that frontal-sensory projection neurons are convergingly vulnerable to multiple ASD risk gene manipulations and are also responsible for cognitive control behaviors. Findings from these studies are expected to establish pre-clinical strategies for ameliorating cognitive deficits in ASD.