Year: 2019
Type: article
Abstract: Autism spectrum disorder (ASD) is currently estimated to affect more than 1% of the world population. For people with ASD, gastrointestinal (GI) distress is a commonly reported but a poorly understood co-occurring symptom. Here, we investigate the physiological basis for GI distress in ASD by studying gut function in a zebrafish model of Phelan-McDermid syndrome (PMS), a condition caused by mutations in the SHANK3 gene. To generate a zebrafish model of PMS, we used CRISPR/Cas9 to introduce clinically related C-terminal frameshift mutations in shank3a and shank3b zebrafish paralogues ( shank3abΔC ). Because PMS is caused by SHANK3 haploinsufficiency, we assessed the digestive tract (DT) structure and function in zebrafish shank3abΔC +/− heterozygotes. Human SHANK3 mRNA was then used to rescue DT phenotypes in larval zebrafish. Significantly slower rates of DT peristaltic contractions ( p < 0.001) with correspondingly prolonged passage time ( p < 0.004) occurred in shank3abΔC +/− mutants. Rescue injections of mRNA encoding the longest human SHANK3 isoform into shank3abΔC +/− mutants produced larvae with intestinal bulb emptying similar to wild type (WT), but still deficits in posterior intestinal motility. Serotonin-positive enteroendocrine cells (EECs) were significantly reduced in both shank3abΔC +/− and shank3abΔC −/− mutants ( p < 0.05) while enteric neuron counts and overall structure of the DT epithelium, including goblet cell number, were unaffected in shank3abΔC +/− larvae. Our data and rescue experiments support mutations in SHANK3 as causal for GI transit and motility abnormalities. Reductions in serotonin-positive EECs and serotonin-filled ENS boutons suggest an endocrine/neural component to this dysmotility. This is the first study to date demonstrating DT dysmotility in a zebrafish single gene mutant model of ASD.
Source: Molecular Autism
Authors: David M. James, Robert A. Kozol, Yuji Kajiwara, Adam L. Wahl, Emily C. Storrs, Joseph D. Buxbaum, Mason Klein, Baharak Moshiree, Julia E. Dallman
Language: English
Subfield: Gastroenterology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,060
Funders: Howard Hughes Medical Institute, Florida Education Fund, University of Miami, Beatrice and Samuel A. Seaver Foundation, National Institutes of Health, National Institute of Mental Health, National Institute of General Medical Sciences, National Institute of Child Health and Human Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development
OpenAlex ID: W2914944728