Abstract
Background and aimsAutism 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.MethodsTo 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.ResultsSignificantly 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.ConclusionsOur 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.
Highlights
Background and aimsAutism spectrum disorder (ASD) is currently estimated to affect more than 1% of the world population
Our work focuses on a monogenic form of ASD, Phelan-McDermid syndrome, that is caused by mutations that disrupt one copy of the SHANK3 gene resulting in SHANK3 haploinsufficiency [9, 10]
Frameshift mutations were induced in both shank3a and shank3b genes, and alleles were selected to minimize the number of amino acids between frameshift and stop codon (Fig. 1c)
Summary
Autism spectrum disorder (ASD) is currently estimated to affect more than 1% of the world population. 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. Autism spectrum disorder (ASD) is estimated to impact more than 1% of the population and is etiologically and clinically heterogeneous [1, 2]. The majority of SHANK3 loss-of-function animal models are mammalian and have provided great insight into neural mechanisms related to social and motor behaviors characteristic of ASD [13]. Studies suggest that SHANK3 may play important GI-related roles in host/symbiont interactions and Zn metabolism [22, 26,27,28] and intestinal barrier function [29]. Studies to explore roles for SHANK3 in relation to GI dysfunction, are limited
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