Gastrointestinal dysfunction in patients and mice expressing the autism-associated r451c mutation in neuroligin-3

Suzanne Hosie, Melina Ellis, Mathusi Swaminathan, Fatima Ramalhosa, Gracia O. Seger, Gayathri K. Balasuriya, Christopher Gillberg, Maria Råstam, Leonid Churilov, Sonja J. McKeown, Nalzi Yalcinkaya, Petri Urvil, Tor Savidge, Carolyn A. Bell, Oonagh Bodin, Jen Wood, Ashley E. Franks, Joel C. Bornstein, Elisa L. Hill-Yardin

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46 Citations (Scopus)


Gastrointestinal (GI) problems constitute an important comorbidity in many patients with autism. Multiple mutations in the neuroligin family of synaptic adhesion molecules are implicated in autism, however whether they are expressed and impact GI function via changes in the enteric nervous system is unknown. We report the GI symptoms of two brothers with autism and an R451C mutation in Nlgn3 encoding the synaptic adhesion protein, neuroligin-3. We confirm the presence of an array of synaptic genes in the murine GI tract and investigate the impact of impaired synaptic protein expression in mice carrying the human neuroligin-3 R451C missense mutation (NL3R451C). Assessing in vivo gut dysfunction, we report faster small intestinal transit in NL3R451C compared to wild-type mice. Using an ex vivo colonic motility assay, we show increased sensitivity to GABAA receptor modulation in NL3R451C mice, a well-established Central Nervous System (CNS) feature associated with this mutation. We further show increased numbers of small intestine myenteric neurons in NL3R451C mice. Although we observed altered sensitivity to GABAA receptor modulators in the colon, there was no change in colonic neuronal numbers including the number of GABA-immunoreactive myenteric neurons. We further identified altered fecal microbial communities in NL3R451C mice. These results suggest that the R451C mutation affects small intestinal and colonic function and alter neuronal numbers in the small intestine as well as impact fecal microbes. Our findings identify a novel GI phenotype associated with the R451C mutation and highlight NL3R451C mice as a useful preclinical model of GI dysfunction in autism. Autism Res 2019.

Original languageEnglish
Pages (from-to)1043-1056
Number of pages14
JournalAutism Research
Issue number7
Publication statusPublished - Jul 2019


  • autism
  • gastrointestinal symptoms
  • gut motility
  • immunofluorescence
  • mouse
  • neuroligin-3

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