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.

Sensory experience and learning refine circuits through elimination of excitatory synapses, a process that depends on activity-driven transcription control and that is deficient in humans with ASD and mouse ASD models. Kimberly Huber and Tae-Kyung Kim will determine the role of ASD-linked epigenetic factors in activity-driven synapse elimination using mouse model systems and identify their gene regulatory networks at the single neuron level.

Exploring the consequences of 16p11.2 deletion in diverse species is key to understanding conserved pathophysiological mechanisms that underly the condition in humans. In the current project, Yann Herault plans to develop a new rat model corresponding to the deletion of the 16p11.2 homologous region in the Long-Evans strain. Comparing similarities and differences between rat and mouse models and humans with 16p11.2 deletion syndrome should not only provide a better understanding of the condition, but also has the potential to foster the development of novel therapeutic approaches.

Hongjun Song will assess whether m⁶A methylation — the most prevalent RNA modification in mammals — regulates the expression of autism risk genes. He will do this by generating a genome-wide map of m⁶A tags in several neural cell types relevant for autism. He will also investigate the potential functional impact of m⁶A tagging on mRNA stability and protein translation of ASD risk genes in both stem cells and animal models.