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Faster Gastrointestinal Transit, Reduced Small Intestinal Smooth Muscle Tone and Dysmotility in the Nlgn3 R451C Mouse Model of Autism

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Τίτλος: Faster Gastrointestinal Transit, Reduced Small Intestinal Smooth Muscle Tone and Dysmotility in the Nlgn3 R451C Mouse Model of Autism
Συγγραφείς: Suzanne Hosie, Tanya Abo-Shaban, Kevin Mou, Gayathri K. Balasuriya, Mitra Mohsenipour, Mohammed U. Alamoudi, Rhiannon T. Filippone, Gabrielle T. Belz, Ashley E. Franks, Joel C. Bornstein, Kulmira Nurgali, Elisa L. Hill-Yardin
Πηγή: International Journal of Molecular Sciences, Vol 25, Iss 2, p 832 (2024)
Στοιχεία εκδότη: MDPI AG
Έτος έκδοσης: 2024
Συλλογή: Directory of Open Access Journals: DOAJ Articles
Θεματικοί όροι: autism, gut dysfunction, gut motility, gut transit, mouse model, Neuroligin-3, Biology (General), QH301-705.5, Chemistry, QD1-999
Περιγραφή: 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 ...
Τύπος εγγράφου: article in journal/newspaper
Γλώσσα: English
Relation: https://www.mdpi.com/1422-0067/25/2/832; https://doaj.org/toc/1661-6596; https://doaj.org/toc/1422-0067; https://doaj.org/article/7b4d1b55652c4aaaa59a3afc96595aaf
DOI: 10.3390/ijms25020832
Διαθεσιμότητα: https://doi.org/10.3390/ijms25020832
https://doaj.org/article/7b4d1b55652c4aaaa59a3afc96595aaf
Αριθμός Καταχώρησης: edsbas.7340F812
Βάση Δεδομένων: BASE
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  Data: Faster Gastrointestinal Transit, Reduced Small Intestinal Smooth Muscle Tone and Dysmotility in the Nlgn3 R451C 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="%22Gayathri+K%2E+Balasuriya%22">Gayathri K. Balasuriya</searchLink><br /><searchLink fieldCode="AR" term="%22Mitra+Mohsenipour%22">Mitra Mohsenipour</searchLink><br /><searchLink fieldCode="AR" term="%22Mohammed+U%2E+Alamoudi%22">Mohammed U. Alamoudi</searchLink><br /><searchLink fieldCode="AR" term="%22Rhiannon+T%2E+Filippone%22">Rhiannon T. Filippone</searchLink><br /><searchLink fieldCode="AR" term="%22Gabrielle+T%2E+Belz%22">Gabrielle T. Belz</searchLink><br /><searchLink fieldCode="AR" term="%22Ashley+E%2E+Franks%22">Ashley E. Franks</searchLink><br /><searchLink fieldCode="AR" term="%22Joel+C%2E+Bornstein%22">Joel C. Bornstein</searchLink><br /><searchLink fieldCode="AR" term="%22Kulmira+Nurgali%22">Kulmira Nurgali</searchLink><br /><searchLink fieldCode="AR" term="%22Elisa+L%2E+Hill-Yardin%22">Elisa L. Hill-Yardin</searchLink>
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  Data: International Journal of Molecular Sciences, Vol 25, Iss 2, p 832 (2024)
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  Data: 2024
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  Data: <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="%22Neuroligin-3%22">Neuroligin-3</searchLink><br /><searchLink fieldCode="DE" term="%22Biology+%28General%29%22">Biology (General)</searchLink><br /><searchLink fieldCode="DE" term="%22QH301-705%2E5%22">QH301-705.5</searchLink><br /><searchLink fieldCode="DE" term="%22Chemistry%22">Chemistry</searchLink><br /><searchLink fieldCode="DE" term="%22QD1-999%22">QD1-999</searchLink>
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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: https://www.mdpi.com/1422-0067/25/2/832; https://doaj.org/toc/1661-6596; https://doaj.org/toc/1422-0067; https://doaj.org/article/7b4d1b55652c4aaaa59a3afc96595aaf
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