The digestive distress that commonly accompanies autism spectrum disorder (ASD) significantly degrades the quality of life of those affected and their families1. In work funded by a SFARI Pilot Award, the Julia Dallman and John Rawls labs used zebrafish models to demonstrate that loss-of-function (lof) mutations in either Shank3 or Syngap1 profoundly impacts gut physiology, both initial nutrient-sensing and subsequent increases in intestinal motility. Using in vivo calcium imaging of sensory enteroendocrine cells (EECs)2, they found that Shank3 and Syngap1 models exhibit muted responses to glucose, indicating altered sensory processing in the gut. In addition, they found deficits in the serotonergic enterochromaffin cells (ECs) that communicate with enteric neurons (ENs), which are known to regulate motility: Shank3 mutants make fewer ECs3 and Syngap1 mutants make fewer ENs. In accord, single cell RNA sequencing shows that Shank3 is enriched in ECs while Syngap1 is enriched in ENs, supporting the idea that Shank3 and Syngap1 play important developmental roles in these cell types.
To build on their findings, they will establish developmental (Aim 1) and physiological (Aim 2) mechanisms linking either Shank3 or Syngap1 lof to digestive dysfunction in ASD models. In Aim 1, they will localize production of Syngap1 and Shank3 isoforms in the cells of gut, compare cell type composition of the intestinal tracts of wild-type (WT) and ASD models using single nucleus RNA sequencing, and determine whether rescuing ASD gene expression in mutants is sufficient to restore WT gut physiology. In Aim 2, they will test the hypothesis that excitation/secretion coupling is disrupted in the glucose-responsive cells of the ASD model guts by quantifying and localizing the mRNAs and proteins that underlie this process and screening for drugs targeting excitation/secretion that can rescue glucose sensing in ASD models. In the long-term, these experiments will identify mechanisms that could serve as future therapeutic targets to ameliorate digestive distress in people with ASD.