The Down-Regulation of Neuroligin-2 and the Correlative Clinical Significance of Serum GABA Over-Expression in Hirschsprung’s Disease

Yang, Hongchao; Niu, Jianyi; Wang, Jian; Zhang, Fan; Zhang, Qiangye; Zhang, Wentong; Li, Aiwu

doi:10.1007/s11064-014-1334-y

Cited by 9 publications

(11 citation statements)

References 25 publications

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“…The anomalies of ENS impaired the motility of the intestine and may lead to NIM finally. This also can explain our previous findings that neurexin and neuroligin are expressed at a significantly downregulated level in the aganglionic segment of HSCR with relative neurotransmitters, Glu and GABA, and unbalance in serum of HSCR [ 27 , 28 ].…”

Section: Discussionmentioning

confidence: 64%

Abundance and Significance of Neuroligin-1 and Neurexin II in the Enteric Nervous System of Embryonic Rats

Wang

Pan

Song

et al. 2017

BioMed Research International

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Aim. To investigate the abundance of neuroligin-1 and neurexin II in the enteric nervous system (ENS) of rats on different embryonic days and to explore their potential significance. Methods. The full-thickness colon specimens proximal to the ileocecal junction of rats on embryonic days 16, 18, and 20 and of newborns within 24 hours (E16, E18, E20, and Ep0) were studied, respectively. qRT-PCR was applied for detecting the expressions of neuroligin-1 and neurexin II on mRNA, and western blotting was employed for detecting their further expressions on the whole tissue. Finally, the histological appearance of neuroligin-1 and neurexin IIα was elucidated using immunohistochemical staining. Results. qRT-PCR showed that the neuroligin-1 and neurexin II mRNA expressions of groups E16, E18, E20, and Ep0 increased gradually with the growth of embryonic rats (P < 0.05). Western blotting confirmed the increasing tendency. In immunohistochemical staining, proteins neuroligin-1 and neurexin IIα positive cells concentrated mostly in the myenteric nerve plexus of the colon and their expressions depend on the embryonic time. Conclusion. Neuroligin-1 and neurexin II were both expressed in the ENS and have temporal correlation with the development of ENS, during which neuronal intestinal malformations (NIM) may occur due to their disruptions and consequent abnormal ENS development.

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Section: Discussionmentioning

confidence: 64%

Abundance and Significance of Neuroligin-1 and Neurexin II in the Enteric Nervous System of Embryonic Rats

Wang

Pan

Song

et al. 2017

BioMed Research International

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“…To clarify potential mechanisms underlying GI dysfunction in neuroligin‐3 linked autism, we characterized expression of neuroligins and their binding partners, the neurexins, in the mouse GI tract. Neuroligins and neurexins are expressed in the rodent [Leembruggen et al, ; Wang et al, ] and human [Wang et al, ; Yang et al, ; Zhang et al, ] GI tract; however, little is known about the functional contribution of neuroligin‐3 expression in the GI tract. Nlgn1 , Nlgn2 , Nlgn3 , Nrxn1 , and Nrxn2 mRNAs are predominantly expressed in myenteric plexus‐enriched preparations of both duodenum and colon (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…These mutations include genes encoding neuroligins, a group of four postsynaptic adhesion molecules (neuroligins‐1 to 4) and their extracellular and intracellular binding partners, neurexins and SHANK3 [Sudhof, ]. Expression of genes encoding several of these proteins is reported in the GI tract [Wang et al, , ; Yang et al, ; Zhang et al, ]; however a systematic analysis of expression in both the small and large intestine and, of particular interest, in neuronal enriched samples is needed.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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 . © 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.

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“…Neuroligin proteins are present in enteric neurons [28][29][30] . As the enteric nervous system plays a major role in regulating gastrointestinal function, we postulated that the R451C mutation would affect motility.…”

Section: Representative Resultsmentioning

confidence: 99%

Video Imaging and Spatiotemporal Maps to Analyze Gastrointestinal Motility in Mice

Swaminathan

Hill‐Yardin

Ellis

et al. 2016

JoVE

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The enteric nervous system (ENS) plays an important role in regulating gastrointestinal (GI) motility and can function independently of the central nervous system. Changes in ENS function are a major cause of GI symptoms and disease and may contribute to GI symptoms reported in neuropsychiatric disorders including autism. It is well established that isolated colon segments generate spontaneous, rhythmic contractions known as Colonic Migrating Motor Complexes (CMMCs). A procedure to analyze the enteric neural regulation of CMMCs in ex vivo preparations of mouse colon is described. The colon is dissected from the animal and flushed to remove fecal content prior to being cannulated in an organ bath. Data is acquired via a video camera positioned above the organ bath and converted to high-resolution spatiotemporal maps via an inhouse software package. Using this technique, baseline contractile patterns and pharmacological effects on ENS function in colon segments can be compared over 3-4 hr. In addition, propagation length and speed of CMMCs can be recorded as well as changes in gut diameter and contraction frequency. This technique is useful for characterizing gastrointestinal motility patterns in transgenic mouse models (and in other species including rat and guinea pig). In this way, pharmacologically induced changes in CMMCs are recorded in wild type mice and in the Neuroligin-3 R451C mouse model of autism. Furthermore, this technique can be applied to other regions of the GI tract including the duodenum, jejunum and ileum and at different developmental ages in mice. Video LinkThe video component of this article can be found at

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The Down-Regulation of Neuroligin-2 and the Correlative Clinical Significance of Serum GABA Over-Expression in Hirschsprung’s Disease

Cited by 9 publications

References 25 publications

Abundance and Significance of Neuroligin-1 and Neurexin II in the Enteric Nervous System of Embryonic Rats

Abundance and Significance of Neuroligin-1 and Neurexin II in the Enteric Nervous System of Embryonic Rats

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

Video Imaging and Spatiotemporal Maps to Analyze Gastrointestinal Motility in Mice

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