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Faster Gastrointestinal Transit, Reduced Small Intestinal Smooth Muscle Tone and Dysmotility in the Nlgn3R451C Mouse Model of Autism

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Title: Faster Gastrointestinal Transit, Reduced Small Intestinal Smooth Muscle Tone and Dysmotility in the Nlgn3R451C Mouse Model of Autism
Authors: Suzanne Hosie, Tanya Abo-Shaban, Kevin Mou, Balasuriya Mudiyanselage Gayathri Kumari Balasuriya, Mitra Mohsenipour, Mohammed Uthman Alamoudi, Rhiannon Filippone, Gabrielle Belz, Ashley Franks, Joel Bornstein, Kulmira Nurgali, Elisa Hill
Publication Year: 2024
Subject Terms: Biochemistry and cell biology not elsewhere classified, Microbiology not elsewhere classified, Neuroligin-3, autism, gut dysfunction, gut motility, gut transit, mouse model, video-imaging
Description: Individuals with autism often experience gastrointestinal issues but the cause is unknown. Many gene mutations that modify neuronal synapse function are associated with autism and therefore may impact the enteric nervous system that regulates gastrointestinal function. A missense mutation in the Nlgn3 gene encoding the cell adhesion protein Neuroligin-3 was identified in two brothers with autism who both experienced severe gastrointestinal dysfunction. Mice expressing this mutation (Nlgn3(R451C) mice) are a well-studied preclinical model of autism and show autism-relevant characteristics, including impaired social interaction and communication, as well as repetitive behaviour. We previously showed colonic dysmotility in response to GABAergic inhibition and increased myenteric neuronal numbers in the small intestine in Nlgn3(R451C) mice bred on a mixed genetic background. Here, we show that gut dysfunction is a persistent phenotype of the Nlgn3 R451C mutation in mice backcrossed onto a C57BL/6 background. We report that Nlgn3(R451C) mice show a 30.9% faster gastrointestinal transit (p = 0.0004) in vivo and have 6% longer small intestines (p = 0.04) compared to wild-types due to a reduction in smooth muscle tone. In Nlgn3(R451C) mice, we observed a decrease in resting jejunal diameter (proximal jejunum: 10.6% decrease, p = 0.02; mid: 9.8%, p = 0.04; distal: 11.5%, p = 0.009) and neurally regulated dysmotility as well as shorter durations of contractile complexes (mid: 25.6% reduction in duration, p = 0.009; distal: 30.5%, p = 0.004) in the ileum. In Nlgn3(R451C) mouse colons, short contractions were inhibited to a greater extent (57.2% by the GABA(A) antagonist, gabazine, compared to 40.6% in wild-type mice (p = 0.007). The inhibition of nitric oxide synthesis decreased the frequency of contractile complexes in the jejunum (WT p = 0.0006, Nlgn3(R451C) p = 0.002), but not the ileum, in both wild-type and Nlgn3(R451C) mice. These findings demonstrate that changes in enteric nervous system function contribute to ...
Document Type: article in journal/newspaper
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Relation: 10779/rmit.27578829.v1; https://figshare.com/articles/journal_contribution/Faster_Gastrointestinal_Transit_Reduced_Small_Intestinal_Smooth_Muscle_Tone_and_Dysmotility_in_the_Nlgn3R451C_Mouse_Model_of_Autism/27578829
Availability: https://figshare.com/articles/journal_contribution/Faster_Gastrointestinal_Transit_Reduced_Small_Intestinal_Smooth_Muscle_Tone_and_Dysmotility_in_the_Nlgn3R451C_Mouse_Model_of_Autism/27578829
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Accession Number: edsbas.6AC6969E
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  – Url: https://figshare.com/articles/journal_contribution/Faster_Gastrointestinal_Transit_Reduced_Small_Intestinal_Smooth_Muscle_Tone_and_Dysmotility_in_the_Nlgn3R451C_Mouse_Model_of_Autism/27578829#
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  Data: Faster Gastrointestinal Transit, Reduced Small Intestinal Smooth Muscle Tone and Dysmotility in the Nlgn3R451C Mouse Model of Autism
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  Data: <searchLink fieldCode="AR" term="%22Suzanne+Hosie%22">Suzanne Hosie</searchLink><br /><searchLink fieldCode="AR" term="%22Tanya+Abo-Shaban%22">Tanya Abo-Shaban</searchLink><br /><searchLink fieldCode="AR" term="%22Kevin+Mou%22">Kevin Mou</searchLink><br /><searchLink fieldCode="AR" term="%22Balasuriya+Mudiyanselage+Gayathri+Kumari+Balasuriya%22">Balasuriya Mudiyanselage Gayathri Kumari Balasuriya</searchLink><br /><searchLink fieldCode="AR" term="%22Mitra+Mohsenipour%22">Mitra Mohsenipour</searchLink><br /><searchLink fieldCode="AR" term="%22Mohammed+Uthman+Alamoudi%22">Mohammed Uthman Alamoudi</searchLink><br /><searchLink fieldCode="AR" term="%22Rhiannon+Filippone%22">Rhiannon Filippone</searchLink><br /><searchLink fieldCode="AR" term="%22Gabrielle+Belz%22">Gabrielle Belz</searchLink><br /><searchLink fieldCode="AR" term="%22Ashley+Franks%22">Ashley Franks</searchLink><br /><searchLink fieldCode="AR" term="%22Joel+Bornstein%22">Joel Bornstein</searchLink><br /><searchLink fieldCode="AR" term="%22Kulmira+Nurgali%22">Kulmira Nurgali</searchLink><br /><searchLink fieldCode="AR" term="%22Elisa+Hill%22">Elisa Hill</searchLink>
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  Data: 2024
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  Data: <searchLink fieldCode="DE" term="%22Biochemistry+and+cell+biology+not+elsewhere+classified%22">Biochemistry and cell biology not elsewhere classified</searchLink><br /><searchLink fieldCode="DE" term="%22Microbiology+not+elsewhere+classified%22">Microbiology not elsewhere classified</searchLink><br /><searchLink fieldCode="DE" term="%22Neuroligin-3%22">Neuroligin-3</searchLink><br /><searchLink fieldCode="DE" term="%22autism%22">autism</searchLink><br /><searchLink fieldCode="DE" term="%22gut+dysfunction%22">gut dysfunction</searchLink><br /><searchLink fieldCode="DE" term="%22gut+motility%22">gut motility</searchLink><br /><searchLink fieldCode="DE" term="%22gut+transit%22">gut transit</searchLink><br /><searchLink fieldCode="DE" term="%22mouse+model%22">mouse model</searchLink><br /><searchLink fieldCode="DE" term="%22video-imaging%22">video-imaging</searchLink>
– Name: Abstract
  Label: Description
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  Data: Individuals with autism often experience gastrointestinal issues but the cause is unknown. Many gene mutations that modify neuronal synapse function are associated with autism and therefore may impact the enteric nervous system that regulates gastrointestinal function. A missense mutation in the Nlgn3 gene encoding the cell adhesion protein Neuroligin-3 was identified in two brothers with autism who both experienced severe gastrointestinal dysfunction. Mice expressing this mutation (Nlgn3(R451C) mice) are a well-studied preclinical model of autism and show autism-relevant characteristics, including impaired social interaction and communication, as well as repetitive behaviour. We previously showed colonic dysmotility in response to GABAergic inhibition and increased myenteric neuronal numbers in the small intestine in Nlgn3(R451C) mice bred on a mixed genetic background. Here, we show that gut dysfunction is a persistent phenotype of the Nlgn3 R451C mutation in mice backcrossed onto a C57BL/6 background. We report that Nlgn3(R451C) mice show a 30.9% faster gastrointestinal transit (p = 0.0004) in vivo and have 6% longer small intestines (p = 0.04) compared to wild-types due to a reduction in smooth muscle tone. In Nlgn3(R451C) mice, we observed a decrease in resting jejunal diameter (proximal jejunum: 10.6% decrease, p = 0.02; mid: 9.8%, p = 0.04; distal: 11.5%, p = 0.009) and neurally regulated dysmotility as well as shorter durations of contractile complexes (mid: 25.6% reduction in duration, p = 0.009; distal: 30.5%, p = 0.004) in the ileum. In Nlgn3(R451C) mouse colons, short contractions were inhibited to a greater extent (57.2% by the GABA(A) antagonist, gabazine, compared to 40.6% in wild-type mice (p = 0.007). The inhibition of nitric oxide synthesis decreased the frequency of contractile complexes in the jejunum (WT p = 0.0006, Nlgn3(R451C) p = 0.002), but not the ileum, in both wild-type and Nlgn3(R451C) mice. These findings demonstrate that changes in enteric nervous system function contribute to ...
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  Data: 10779/rmit.27578829.v1; https://figshare.com/articles/journal_contribution/Faster_Gastrointestinal_Transit_Reduced_Small_Intestinal_Smooth_Muscle_Tone_and_Dysmotility_in_the_Nlgn3R451C_Mouse_Model_of_Autism/27578829
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  Label: Availability
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  Data: https://figshare.com/articles/journal_contribution/Faster_Gastrointestinal_Transit_Reduced_Small_Intestinal_Smooth_Muscle_Tone_and_Dysmotility_in_the_Nlgn3R451C_Mouse_Model_of_Autism/27578829
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  Data: edsbas.6AC6969E
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    Subjects:
      – SubjectFull: Biochemistry and cell biology not elsewhere classified
        Type: general
      – SubjectFull: Microbiology not elsewhere classified
        Type: general
      – SubjectFull: Neuroligin-3
        Type: general
      – SubjectFull: autism
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      – SubjectFull: gut dysfunction
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      – SubjectFull: gut motility
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      – SubjectFull: gut transit
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      – TitleFull: Faster Gastrointestinal Transit, Reduced Small Intestinal Smooth Muscle Tone and Dysmotility in the Nlgn3R451C Mouse Model of Autism
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              Y: 2024
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