While clinical and pathological studies of individuals diagnosed with ASD have repeatedly implicated the cerebellum in ASD pathogenesis, whole-tissue analyses have not found differences in gene expression between ASD and unaffected cerebellar tissue. Kathleen Millen, in collaboration with Kimberly Aldinger, plans to use state-of-the-art single-cell and bulk tissue RNA sequencing to fully define the molecular and cellular diversity across all cell types within the cerebellum in ASD.

Tingting Wang will examine the role of the autism risk gene CHD2 in glia and identify downstream targets regulating homeostatic synaptic plasticity by using both in vitro and in vivo systems, including Drosophila and mice. This work will provide a better understanding of the role of CHD2 and glia-signaling pathways in autism.

Larry Zweifel and Bill Catterall have identified de novo autism missense mutations in several voltage-gated ion channels that map to key residues critical for providing their voltage-sensing abilities. Using bacterial channels and mutant mouse model systems, they will establish how these mutations alter biophysical properties of these ion channels and lead to cellular and systems level dysfunctions that ultimately contribute to phenotypes associated with autism.

Several lines of evidence suggest that neurogenesis during brain development is disrupted in autism, but the mechanisms are unclear. Jeremy Willsey and Martin Kampmann will leverage advances in stem cell technology and CRISPR-based genetic approaches to understand the intersection between autism risk genes and neurogenesis, with the goal of determining whether common molecular pathways underlie the pathogenesis of autism.

Autism spectrum disorder (ASD) is diagnosed four times as often in boys compared than girls, but the developmental mechanisms that lead to this male bias have not been elucidated. Jessica Tollkuhn recently identified 13 high-confidence ASD risk genes that exhibited increased expression in two sexually dimorphic brain regions of female mice compared to males. The goal of the current project is to determine if this female bias in expression of ASD risk genes extends to cortical brain regions and is restricted to specific cell types, with the long-term goal of understanding female resiliency to developing ASD.

Denis Jabaudon aims to trace abnormal developmental trajectories of neocortical progenitors and their progeny in a 22q11.2 deletion syndrome mouse model in order to identify potential developmental hot spots amendable to therapeutic interventions for ASD.