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.

Alterations in FOXP1 are associated with ASD and mouse models suggest that Foxp1 is important for striatal development and function. Genevieve Konopka and Jay Gibson will use a combination of molecular and electrophysiological methods to investigate how cell-type specific deletions of Foxp1 affect striatal cell fate, survival and function in mice.

Stephen Scherer will study the effects of mutations in the PTCHD1-AS long noncoding RNA gene, a candidate ASD risk gene, using induced pluripotent stem cells and mouse models. Results from these studies are expected to provide new insights into molecular and physiological events underlying ASD pathogenesis.

Using a mouse model of fragile X syndrome, Hye Young Lee aims to understand the molecular mechanisms by which FMRP causes microglia dysfunction and to elucidate the effects of Fmr1 mutations on microglia-neuron communication under basal conditions as well as after neuroinflammation.

Tuberous sclerosis complex (TSC) and fragile X syndrome are syndromic neurogenetic disorders that have a high prevalence of ASD; however, the relationship between these two disorders at the cellular level has so far been largely unexplored. FMRP is known to be downregulated in neurons that lack TSC2. Mustafa Sahin plans to build on these findings and investigate the underlying mechanisms that are responsible for downregulating FMRP expression, using both induced pluripotent stem cells from individuals with tuberous sclerosis complex and Tsc2-deficient mice.