Gastrointestinal dysfunction in patients and mice expressing the autism-associated R451C mutation in neuroligin-3

• 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 (NL3(R451C)). Assessing in vivo gut dysfunction, we report faster small intestinal transit in NL3(R451C) compared to wild-type mice. Using an ex vivo colonic motility assay, we show increased sensitivity to GABA(A) receptor modulation in NL3(R451C) mice, a well-established Central Nervous System (CNS) feature associated with this mutation. We further show increased numbers of small intestine myenteric neurons in NL3(R451C) mice. Although we observed altered sensitivity to GABA(A) 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 NL3(R451C) 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(R451C) mice as a useful preclinical model of GI dysfunction in autism. Autism Res 2019, 12: 1043-1056. (c) 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medical Genetics (hsv//eng)

Nyckelord

autism

gastrointestinal symptoms

gut motility

immunofluorescence

mouse

neuroligin-3

enteric nervous-system

gamma-aminobutyric acid

synaptic-transmission

spectrum disorder

colonic motility

gut-brain

children

neurons

abnormalities

microbiota

Behavioral Sciences

Psychology

erubini e

1984

british journal of pharmacology

v82

p93

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)