Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/20848
Title: Gastrointestinal dysfunction in patients and mice expressing the autism-associated R451C mutation in neuroligin-3.
Authors: Hosie, Suzanne;Ellis, Melina;Swaminathan, Mathusi;Ramalhosa, Fatima;Seger, Gracia O;Balasuriya, Gayathri K;Gillberg, Christopher;Råstam, Maria;Churilov, Leonid;McKeown, Sonja J;Yalcinkaya, Nalzi;Urvil, Petri;Savidge, Tor;Bell, Carolyn A;Bodin, Oonagh;Wood, Jen;Franks, Ashley E;Bornstein, Joel C;Hill-Yardin, Elisa L
Affiliation: The Florey Institute of Neuroscience and Mental Health, Heidelberg, Victoria, Australia
Texas Children's Microbiome Center, Texas Children's Hospital and Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas
School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia
Life and Health Sciences Research Institute, University of Minho, Braga, Portugal
Gillberg Neuropsychiatry Centre, Institute of Neuroscience and Physiology, University of Gothenburg, Göteborg, Sweden
Department of Clinical Sciences Lund, Child and Adolescent Psychiatry, Lund University, Lund, Sweden
Department of Physiology, The University of Melbourne, Parkville, VIC, Australia
Cancer Program, Monash Biomedicine Discovery Institute, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia
La Trobe University, Department of Physiology, Anatomy & Microbiology, School of Life Sciences, Bundoora, VIC, Australia
School of Science Cluster, RMIT University, Melbourne City Campus, Melbourne, VIC, Australia
Issue Date: 22-May-2019
EDate: 2019-05-22
Citation: Autism Research 2019; online first: 22 May
Abstract: 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. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with autism commonly experience gastrointestinal problems, however the cause is unknown. We report gut symptoms in patients with the autism-associated R451C mutation encoding the neuroligin-3 protein. We show that many of the genes implicated in autism are expressed in mouse gut. The neuroligin-3 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.
URI: http://ahro.austin.org.au/austinjspui/handle/1/20848
DOI: 10.1002/aur.2127
ORCID: 0000-0001-8569-2912
0000-0003-3411-4543
0000-0001-8848-1934
0000-0003-0819-3946
0000-0002-7318-116X
0000-0003-1664-6060
0000-0002-7518-7717
PubMed URL: 31119867
Type: Journal Article
Subjects: autism
gastrointestinal symptoms
gut motility
immunofluorescence
mouse
neuroligin-3
Appears in Collections:Journal articles

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