Gordon Fishell and Jordane Dimidschstein will combine human genetic data with large-scale transcriptomic and epigenetic analyses to assess how alterations in autism risk genes affect biological processes occurring within GABAergic and cholinergic neuronal populations during the early stages of fate specification.

Denis Sukhodolsky and Kevin Pelphrey will perform a randomized clinical trial of oxytocin to determine if it can enhance responses to Pivotal Response Training in young children with autism. Functional magnetic resonance brain imaging and eye tracking measures will be studied in conjunction with key behavioral outcomes. This study will aid in the development of more precise treatments for children with ASD that are guided by objective neurobiological markers.

Using identical visual stimulation protocols in mice and children — both typically developing and those possessing homologous ASD-associated genetic mutations — Mark Bear and Charles Nelson aim to identify behavioral and neurophysiological biomarkers that could accelerate diagnosis and elucidate new therapeutic targets for ASD.

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.

Haiyuan Yu, Bernie Devlin and Kathryn Roeder aim to develop an experimentally and computationally integrated interactome perturbation screening pipeline and additional analytical methods to study the functional impact of de novo missense mutations in autism.

Jess Cardin and Michael J. Higley will establish a functional screen (using a CRISPR/Cas9-induced gene disruption system and multiscale in vivo calcium imaging in awake mice) for the assessment of common cellular- and circuit-level cortical dysregulation phenotypes associated with mutations in ASD risk genes.

Joseph Dougherty will assess the functional consequences of mutations in untranslated regions (UTRs), furthering our understanding of the risk burden of noncoding variants in ASD. This project is part of a number of linked projects within the SSC-ASC Whole-Genome Sequencing Consortium.

Joseph Gleeson proposes to measure gonadal mosaicism for the presence of ASD-causative mutations. He also plans to use this information to stratify males into those with baseline risk and those with high risk of fathering a child with ASD.

Studying the development of the human midfetal prefrontal cortex (PFC) is integral to understanding the pathophysiology of ASD. Nenad Sestan aims to generate a multispecies comprehensive tissue-level and single-cell profile of the midfetal PFC to identify pertinent gene regulatory pathways and candidate genes. The function of identified ASD-relevant pathways will then be assessed in CRISPR-based targeted deletion/insertion mouse lines.

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.