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Interactions of the Enteric Nervous System with the Gut Microbiome in the Neuroligin-3 R451C Mouse Model of Autism

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Interactions of the Enteric Nervous System with the Gut Microbiome in the Neuroligin-3 R451C Mouse Model of Autism Interactions of the enteric nervous system with the gut microbiome in the neuroligin-3R451C mouse model of autism M.H.M. Madusani Herath Submitted in total fulfilment of the requirements of the degree of Doctor of Philosophy September 2020 Department of Physiology The University of Melbourne ABSTRACT Autism patients are four times more likely to be hospitalized due to gastrointestinal (GI) dysfunction compared to the general public. However, the exact cause of GI dysfunction in individuals with autism is currently unknown. Genetic predisposition to autism spectrum disorder (ASD) has been highlighted in various studies and mutations in genes that affect nervous system function can drive both behavioural abnormalities and GI dysfunction in autism. Neuroligin-3 (NLGN3) is a postsynaptic membrane protein and the R451C missense mutation in the NLGN3 gene is associated with ASD. Recent studies revealed that the NLGN3 R451C mutation induces GI dysfunction in autism patients as well as in mice but, the cellular localization and the effects of this mutation on NLGN3 production in the enteric nervous system (ENS) have not been reported to date. The intestinal mucosal barrier is the interface separating the external environment from the interior of the body. Mucosal barrier functions are directly regulated by the enteric nervous system. Therefore, ENS dysfunction can induce mucosal barrier impairments. An impaired intestinal barrier has been reported in autism patients, but neurally-mediated barrier dysfunctions have not been assessed in transgenic autism mouse models with an altered nervous system. The intestinal mucus layer is the outermost layer of the mucosa which separates the intestinal microbiota from the intestinal epithelium. The mucus layer also serves as an energy source for mucus-residing microbes in the intestine. Although the composition of mucus-residing microbiota is altered in a subset of autism patients, the underlying physiological interactions between the host and these microbes are unclear. Identifying the precise spatial location of microbial populations in the gut is essential in order to understand host-microbial interactions but this has not been investigated in Nlgn3R451C mice. In Chapter 3, I developed a method combining RNAScope in situ hybridization and immunohistochemistry technique to localize Nlgn3 mRNA in enteric neuronal subpopulations and glia. Further, a 3-dimensional quantitative image analysis method was developed to measure the Nlgn3 mRNA expression in the ENS. The same protocol was used to determine the effects of the Nlgn3 R451C mutation on Nlgn3 mRNA synthesis in the enteric nervous system. Findings from this study showed that, Nlgn3 mRNA is expressed in most submucosal and myenteric neurons in the ENS. Interestingly, this study revealed for the first time that Nlgn3 mRNA is expressed in enteric glia. In addition, analysis from this study demonstrated that the R451C mutation reduces Nlgn3 mRNA expression in most enteric neurons in mutant mice compared to WT. In Chapter 4, I investigated the effects of the Nlgn3 R451C mutation on intestinal mucosal barrier functions including the paracellular pathway and mucosal secretion in the small intestine. The Ussing chamber technique was used to measure the paracellular permeability and mucosal secretion ex vivo. Since the paracellular pathway is regulated by tight junctions, effects of this mutation on tight junction protein gene expression were measured using real- time (RT) PCR array and droplet digital (dd) PCR approaches. The impact of the Nlgn3 R451C mutation on the neurochemistry of the submucosal plexus was examined using immunocytochemistry. Results from these experiments indicated that the R451C mutation increases paracellular permeability and decreases transepithelial resistance (TER) in the distal ileum. However, ileal tight junction protein gene expression is unchanged in mutant mice compared to WT. Pharmacological stimulation of submucosal ganglia decreased the neurally- evoked mucosal secretion in mutant mice compared to WT. In addition, immunohistochemistry data revealed increased numbers of non-cholinergic and decreased cholinergic neuronal populations in the submucosal plexus in the distal ileum but not in the jejunum in Nlgn3R451C mutant mice. i Given that, I identified altered barrier functions in the distal ileum of Nlgn3R451C mutant mice, in chapter 5, I also analysed the spatial distribution of the mucus-residing microbial populations in this region. To determine the spatial distribution of total bacteria, phylum Bacteroidetes, phylum Firmicutes, Akkermansia muciniphila (A. muciniphila) and Bacteroides thetaiotamicron (B. thetaiotamicron) were labelled using fluorescent in situ hybridization. Immunofluorescence for the mucin-2 protein was incorporated to co-stain the mucus and determine the thickness of the mucus layer. Both the spatial pattern of microbial populations and mucus layer thickness were analysed using MATLAB-based BacSpace software. Immunofluorescence experiments revealed that the R451C mutation increases mucus density adjacent to the epithelium. Along with increased mucus density, the total bacterial density was higher in the mucosa in mutant mice. Further, a decreased ratio of Bacteroidetes/Firmicutes, a decreased A. muciniphila density and increased density of B. thetaiotamicron were observed in mutant mice. Overall, findings from this thesis revealed that NLGN3 is expressed in the enteric nervous system and that the R451C mutation reduces Nlgn3 mRNA expression levels in enteric neurons. Furthermore, the Nlgn3 R451C mutation impairs intestinal mucosal barrier integrity. Findings from this study also revealed that this mutation alters mucus density as well as the spatial distribution and composition of the microbial community in the distal ileum in mice. Therefore, these findings highlight that an autism-associated gene mutation that affects nervous system function impairs the mucosal barrier and may contribute to the pathophysiology of GI dysfunction in ASD. ii DECLARATION This is to certify that: • this thesis comprises only my original work except where indicated in the preface, • due acknowledgement has been made in the text to all other material used, • this thesis is less than 100,000 in length, inclusive of footnotes, but exclusive of tables, maps, appendices and bibliography Madusani Herath September 2020 iii PREFACE Under my direction, the following people have made the stated contributions to my work: Chapter 3: All the experiments in this chapter were conducted by me. Technical assistance and advice for RNAScope data analysis was provided by Dr. Ellie Cho, Biological Optical Microscopy Platform, The University of Melbourne. Chapter 4: All the experiments in this chapter were conducted by me. Technical assistance and advice for Ussing chamber, immunohistochemistry was provided by Ms. Pavitha Parathan. Some technical assistance for RT-PCR array was provided by Dr. Andrew Jobling and Dr. Gayathri Balasuriya. Technical assistance for droplet digital PCR was provided by Ms. Franca Casagranda. Chapter 5: All the experiments in this chapter were conducted by me. Technical assistance and advice for fluorescent in situ hybridization was provided by Dr. Lucie Semenec. iv Publications arising from this thesis include: Herath, M., Hosie, S., Bornstein, J. C., Franks, A. E., & Hill-Yardin, E. L. (2020). The Role of the Gastrointestinal Mucus System in Intestinal Homeostasis: Implications for Neurological Disorders. Frontiers in Cellular and Infection Microbiology, 10, 248. Abstracts (refereed*) Herath, M., Franks, A.E., Bornstein, J.C., Hill-Yardin, E.L. (2019) Neuronal regulation of mucosal barrier function in the neuroligin-3R451C mouse model of autism. Australasian Neuroscience Society, Adelaide, Australia. Herath, M., Franks, A.E., Bornstein, J.C., Hill-Yardin, E.L. (2018) Investigating the mucosal barrier function in the Neuroligin-3R451C mouse model of autism. Australasian Neuroscience Society, Brisbane, Australia. Herath, M., Leembruggen. A., Seger.G., Franks, A.E., Bornstein, J.C., Hill-Yardin, E.L. (2017) Investigating the interactions between the gut microbiome and the enteric nervous system in autism, Australasian Society for Autism Research, Melbourne, Australia. v ACKNOWLEDGMENTS My PhD journey has been a challenging and truly life-changing experience for me, and this thesis would not have been possible without the support and guidance that I received from many knowledgeable, generous and kind people. Firstly, I would like to express my sincere gratitude to my supervisors Prof. Joel Bornstein, A/Prof. Elisa Hill-Yardin and Prof. Ashley Franks. Joel, thank you so much for having me in your lab and thank you for your guidance, support and advice. Your expertise and insightful feedback changed the way I think and helped me to bring this work to a higher level. Elisa, thank you so much for your guidance and support during this journey. I would like to thank you for sharing invaluable non-academic opportunities with me which will help immensely with my next career path. Ashley, thank you so much for your guidance and support and thank you so much for taking time out of your busy schedule to support my work. I would like to thank my advisory committee, A/Prof. Rene Koopman, A/Prof. Vicky Lawson and Prof. Andrew Allen for reviewing my progress and giving me feedback, suggestions and advice. I also would like to thank the Department of Physiology. It has been a great pleasure to work with such amazing people.
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