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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\n                      <jats:italic>Nlgn3<\/jats:italic>\n                      encoding the synaptic adhesion protein, neuroligin\u20103. 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\u20103 R451C missense mutation (NL3\n                      <jats:sup>R451C<\/jats:sup>\n                      ). Assessing in vivo gut dysfunction, we report faster small intestinal transit in NL3\n                      <jats:sup>R451C<\/jats:sup>\n                      compared to wild\u2010type mice. Using an ex vivo colonic motility assay, we show increased sensitivity to GABA\n                      <jats:sub>A<\/jats:sub>\n                      receptor modulation in NL3\n                      <jats:sup>R451C<\/jats:sup>\n                      mice, a well\u2010established Central Nervous System (CNS) feature associated with this mutation. We further show increased numbers of small intestine myenteric neurons in NL3\n                      <jats:sup>R451C<\/jats:sup>\n                      mice. Although we observed altered sensitivity to GABA\n                      <jats:sub>A<\/jats:sub>\n                      receptor modulators in the colon, there was no change in colonic neuronal numbers including the number of GABA\u2010immunoreactive myenteric neurons. We further identified altered fecal microbial communities in NL3\n                      <jats:sup>R451C<\/jats:sup>\n                      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 NL3\n                      <jats:sup>R451C<\/jats:sup>\n                      mice as a useful preclinical model of GI dysfunction in autism.\n                      <jats:italic>\n                        <jats:bold>Autism Res<\/jats:bold>\n                        2019, 12: 1043\u20131056\n                      <\/jats:italic>\n                      . \u00a9 2019 International Society for Autism Research, Wiley Periodicals, Inc.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Lay Summary<\/jats:title>\n                    <jats:p>People with autism commonly experience gastrointestinal problems, however the cause is unknown. We report gut symptoms in patients with the autism\u2010associated R451C mutation encoding the neuroligin\u20103 protein. We show that many of the genes implicated in autism are expressed in mouse gut. The neuroligin\u20103 R451C mutation alters the enteric nervous system, causes gastrointestinal dysfunction, and disrupts gut microbe populations in mice. Gut dysfunction in autism could be due to mutations that affect neuronal communication.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/aur.2127","type":"journal-article","created":{"date-parts":[[2019,5,23]],"date-time":"2019-05-23T02:37:00Z","timestamp":1558579020000},"page":"1043-1056","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":89,"title":["Gastrointestinal dysfunction in patients and mice expressing the autism\u2010associated R451C mutation in neuroligin\u20103"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8569-2912","authenticated-orcid":false,"given":"Suzanne","family":"Hosie","sequence":"first","affiliation":[{"name":"School of Health and Biomedical Sciences RMIT University  Bundoora VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melina","family":"Ellis","sequence":"additional","affiliation":[{"name":"Department of Physiology The University of Melbourne  Parkville VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathusi","family":"Swaminathan","sequence":"additional","affiliation":[{"name":"Department of Physiology The University of Melbourne  Parkville VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima","family":"Ramalhosa","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute, University of Minho  Braga Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gracia O.","family":"Seger","sequence":"additional","affiliation":[{"name":"Department of Physiology The University of Melbourne  Parkville VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3411-4543","authenticated-orcid":false,"given":"Gayathri K.","family":"Balasuriya","sequence":"additional","affiliation":[{"name":"School of Health and Biomedical Sciences RMIT University  Bundoora VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8848-1934","authenticated-orcid":false,"given":"Christopher","family":"Gillberg","sequence":"additional","affiliation":[{"name":"Gillberg Neuropsychiatry Centre Institute of Neuroscience and Physiology, University of Gothenburg  G\u00f6teborg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0819-3946","authenticated-orcid":false,"given":"Maria","family":"R\u00e5stam","sequence":"additional","affiliation":[{"name":"Gillberg Neuropsychiatry Centre Institute of Neuroscience and Physiology, University of Gothenburg  G\u00f6teborg Sweden"},{"name":"Department of Clinical Sciences Lund Child and Adolescent Psychiatry, Lund University  Lund Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonid","family":"Churilov","sequence":"additional","affiliation":[{"name":"School of Science Cluster RMIT University, Melbourne City Campus  Melbourne VIC Australia"},{"name":"Florey Institute of Neuroscience and Mental Health  Heidelberg VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7318-116X","authenticated-orcid":false,"given":"Sonja J.","family":"McKeown","sequence":"additional","affiliation":[{"name":"Cancer Program, Monash Biomedicine Discovery Institute, Department of Anatomy and Developmental Biology Monash University  Clayton VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nalzi","family":"Yalcinkaya","sequence":"additional","affiliation":[{"name":"Texas Children's Microbiome Center, Texas Children's Hospital and Department of Pathology and Immunology Baylor College of Medicine  Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petri","family":"Urvil","sequence":"additional","affiliation":[{"name":"Texas Children's Microbiome Center, Texas Children's Hospital and Department of Pathology and Immunology Baylor College of Medicine  Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tor","family":"Savidge","sequence":"additional","affiliation":[{"name":"Texas Children's Microbiome Center, Texas Children's Hospital and Department of Pathology and Immunology Baylor College of Medicine  Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn A.","family":"Bell","sequence":"additional","affiliation":[{"name":"La Trobe University, Department of Physiology, Anatomy &amp; 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