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

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Number of pages14
JournalAutism Research
DOIs
Publication statusAccepted/In press - 22 May 2019

Keywords

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

Cite this

Hosie, S., Ellis, M., Swaminathan, M., Ramalhosa, F., Seger, G. O., Balasuriya, G. K., ... Hill-Yardin, E. L. (Accepted/In press). Gastrointestinal dysfunction in patients and mice expressing the autism-associated r451c mutation in neuroligin-3. Autism Research. https://doi.org/10.1002/aur.2127
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. / Gastrointestinal dysfunction in patients and mice expressing the autism-associated r451c mutation in neuroligin-3. In: Autism Research. 2019.
@article{eed82169d2b94364aab6cb5df5a4c786,
title = "Gastrointestinal dysfunction in patients and mice expressing the autism-associated r451c mutation in neuroligin-3",
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.",
keywords = "autism, gastrointestinal symptoms, gut motility, immunofluorescence, mouse, neuroligin-3",
author = "Suzanne Hosie and Melina Ellis and Mathusi Swaminathan and Fatima Ramalhosa and Seger, {Gracia O.} and Balasuriya, {Gayathri K.} and Christopher Gillberg and Maria R{\aa}stam and Leonid Churilov and McKeown, {Sonja J.} and Nalzi Yalcinkaya and Petri Urvil and Tor Savidge and Bell, {Carolyn A.} and Oonagh Bodin and Jen Wood and Franks, {Ashley E.} and Bornstein, {Joel C.} and Hill-Yardin, {Elisa L.}",
year = "2019",
month = "5",
day = "22",
doi = "10.1002/aur.2127",
language = "English",
journal = "Autism Research",
issn = "1939-3792",
publisher = "Wiley-Blackwell",

}

Hosie, S, Ellis, M, Swaminathan, M, Ramalhosa, F, Seger, GO, Balasuriya, GK, Gillberg, C, Råstam, M, Churilov, L, McKeown, SJ, Yalcinkaya, N, Urvil, P, Savidge, T, Bell, CA, Bodin, O, Wood, J, Franks, AE, Bornstein, JC & Hill-Yardin, EL 2019, 'Gastrointestinal dysfunction in patients and mice expressing the autism-associated r451c mutation in neuroligin-3' Autism Research. https://doi.org/10.1002/aur.2127

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

In: Autism Research, 22.05.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Gastrointestinal dysfunction in patients and mice expressing the autism-associated r451c mutation in neuroligin-3

AU - Hosie, Suzanne

AU - Ellis, Melina

AU - Swaminathan, Mathusi

AU - Ramalhosa, Fatima

AU - Seger, Gracia O.

AU - Balasuriya, Gayathri K.

AU - Gillberg, Christopher

AU - Råstam, Maria

AU - Churilov, Leonid

AU - McKeown, Sonja J.

AU - Yalcinkaya, Nalzi

AU - Urvil, Petri

AU - Savidge, Tor

AU - Bell, Carolyn A.

AU - Bodin, Oonagh

AU - Wood, Jen

AU - Franks, Ashley E.

AU - Bornstein, Joel C.

AU - Hill-Yardin, Elisa L.

PY - 2019/5/22

Y1 - 2019/5/22

N2 - 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.

AB - 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.

KW - autism

KW - gastrointestinal symptoms

KW - gut motility

KW - immunofluorescence

KW - mouse

KW - neuroligin-3

UR - http://www.scopus.com/inward/record.url?scp=85066881306&partnerID=8YFLogxK

U2 - 10.1002/aur.2127

DO - 10.1002/aur.2127

M3 - Article

JO - Autism Research

JF - Autism Research

SN - 1939-3792

ER -