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Neural Mechanisms Involved in Enterotoxin- Induced Intestinal Hypersecretion

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Neural Mechanisms Involved in Enterotoxin- Induced Intestinal Hypersecretion NEURAL MECHANISMS INVOLVED IN ENTEROTOXIN- INDUCED INTESTINAL HYPERSECRETION Katerina Koussoulas BSc, MSc UMelb. Submitted in total fulfillment of the requirements of the degree of Doctor of Philosophy November 2017 Department of Physiology The University of Melbourne ABSTRACT Exotoxins of the bacteria Vibrio cholerae (cholera toxin, CT) and Clostridium difficile (C. diff., TcdA) induce rampant disease in the form of irresolvable diarrhoea causing rapid dehydration and potential death if left untreated. Both bacterial toxins affect the nervous system of the gut, the enteric nervous system (ENS), but the types of enteric neurons involved are still indistinct. Additionally, preliminary work from a collaborator showed that specific bacterial metabolites, particularly GABA produced by the microorganisms residing in the gut, exacerbate pathophysiological effects of C. diff. GABA and its receptors are expressed in several parts of the gut wall, including enteric neurons. While studies have proposed GABA to be a putative neurotransmitter in the ENS, physiological roles of GABA in the gut remain unclear. It is unknown how enterotoxins and increased GABA at the level of the gut mucosa activate underlying enteric circuitry; my PhD aimed to elucidate these mechanisms. In Chapter 3, I investigated the enteric neural pathways underlying CT effects via in vitro incubations of CT in guinea pig jejunum. Previous work highlighted the impacts of CT on secretomotor neurons; I endeavoured to expand this by examining other key neuronal subtypes. I recorded neuronal activity in the myenteric plexus (MP) up to 6 hours after CT incubation via intracellular electrophysiology. A colleague undertook similar recordings in the submucosal plexus (SMP). We found that CT induced hyperexcitability in myenteric, but not submucosal, sensory neurons. The effect was neurally mediated and required activation of NK3 tachykinin receptors, but was independent of activation of 5-HT3 receptors or NK1 tachykinin receptors, suggesting that the effects of CT on myenteric sensory neurons are likely to be indirect and via a pathway independent of 5-HT release. In Chapter 4, I determined the effects of luminal incubations TcdA and GABA on myenteric sensory neurons via electrophysiology. I found that in vitro incubations of guinea pig jejuna with TcdA or GABA also increased the excitability of myenteric sensory neurons, highlighting the key role of these neurons as a common point through which enterotoxins and GABA operate. The GABA-induced effects were inhibited by GABAB and GABAC receptor antagonists, but enhanced by a GABAA antagonist, i indicating involvement of at least two distinct GABA activated pathways. The GABAA antagonist enhanced excitability on its own suggesting that tonic release of endogenous GABA may play a role in suppressing the excitability of these neurons. In Chapter 5, I explored the role of endogenous GABA in the ENS of mouse small intestine. I employed Wnt1-Cre;R26R-GCaMP3 mice, which express a fluorescent calcium indicator in the ENS, for use in Ca2+ imaging. Neurons responded to GABA exposure via activation of GABAA, GABAB and GABAC receptors in myenteric ganglia. Further, I showed that the effects of GABA were neuronal subtype specific, for example neurons immunoreactive for neuronal nitric oxide synthase rarely responded to GABA. I also demonstrated that endogenous release of GABA may inhibit activation of myenteric neurons by activation of GABAC receptors, despite such receptors exciting myenteric neurons when activated by exogenous GABA. My data also suggest that neither GABAA nor GABAB receptors contribute to synaptic transmission in this system. Further I also demonstrated the expression of GABA in neurons and varicosities surrounding specific enteric neurons within the MP. This study clarifies the complex nature of GABAergic transmission in the ENS. In Chapter 6 to further examine the effects of enterotoxins on the enteric circuitry, I made intracellular recordings from myenteric neurons following in vivo incubations of CT in mouse ileal loops. A lab member previously showed that CT increases calcium responses in the submucosal but not myenteric, neurons. In undertaking electrophysiological recordings, a striking sampling bias was revealed with exclusion of largely descending interneurons and inhibitory motor neurons being markedly underrepresented in the data set and low sampling from sensory neurons meant that significant effects in excitability may have been missed. Nevertheless in concordance with the results from Ca2+ imaging, no significant changes in excitability of myenteric neurons were found at their resting membrane potential. However, CT induced spontaneous synaptic activity in specific myenteric neurons, but the sources of this input could not be identified due to the technical difficulty of maintaining impalements, the relative rarity of myenteric sensory neurons and the sampling bias. The data suggest a minor role for myenteric neurons in CT-induced hypersecretion in vivo. ii In Chapter 7 I employed the high throughput assay of Ca2+ imaging to perform a more extensive examination of the effects of TcdA on the ENS. I utilized the well-established ileal loop mouse model and incubated TcdA in vivo. Spontaneous and neurally- stimulated calcium responses were reduced in submucosal neurons, and myenteric neuronal activity was unchanged. However enteric neurons in regions of the gastrointestinal tract off-target from the site of acute toxin exposure were activated during the incubation as indicated by expression of activity dependent markers. This off target effect could possibly be due to release of inflammatory cytokines into the circulation or extrinsic neural pathways. In all, I have demonstrated a generality in the actions of enterotoxins and GABA as the pathways they activate converge to excite myenteric sensory neurons which may lead to activation of submucosal secretomotor neurons. I have extended our understanding of the role of GABA in the ENS as a means to elucidate the mechanisms through which microbial metabolites act and contribute to disease. Using the mouse ileal loop model, I further defined the effects of enterotoxins on the enteric circuitry. In this way, my thesis highlights neural elements involved in the mechanisms underlying enterotoxin-induced hypersecretion and identifies potential avenues for future research. iii 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; and • the thesis is less than 100,000 words in length, inclusive of footnotes, but exclusive of tables, maps, appendices and bibliography. Katerina Koussoulas November 2017 iv PREFACE Under my direction, the following people have made the stated contributions to this work: Chapter 3: I undertook 50% of the intracellular recording experiments, about half of these were conducted during my Masters (MSc). Ms Rachel Gwynne performed 50% of the intracellular recording experiments including some myenteric and all submucosal neurons. I performed 60% of the data analysis. Assistance in preparing the manuscript for this chapter for publication was provided by Prof Joel Bornstein, Dr Jaime Foong and Ms Rachel Gwynne. Chapter 4: I undertook 90% of the intracellular recordings and all data analysis. Dr Jaime Foong performed 2 intracellular recording experiments, Ms Rachel Gwynne performed 3 intracellular recording experiments. Technical assistance and advice on use of TcdA was provided by A/Prof. Tor Savidge. Chapter 5: I undertook 75% of the calcium imaging experiments, immunohistochemistry and data analysis. Dr Jaime Foong performed some calcium imaging experiments with drug antagonists and some post-hoc immunohistochemical experiments. Calcium imaging preparations were rung by Ms Candice Fung. Technical assistance and advice on calcium imaging experiments and immunohistochemistry was provided by Dr Jaime Foong. Dr Jaime Foong and Ms Mathusi Swaminathan imaged and analysed GABAergic varicosities. Chapter 6: I performed 80% of the ileal loop surgeries and undertook 100% of the intracellular recordings and data analysis. Technical assistance with mouse surgeries was provided by Prof Andrew Allen and Ms Candice Fung. Ms Petra Unterweger performed some surgeries. Chapter 7: I performed all ileal loop surgeries and undertook 100% of the experiments and data analysis for calcium imaging and immunohistochemistry. Ms Candice Fung rung preparations for calcium imaging and performed all Ussing chamber experiments and associated data analysis. Technical assistance and advice on cell culture for TcdA cytotoxicity assays was provided by Dr Marissa Caldow. v Publications arising from this thesis include: Koussoulas, K., Gwynne, R.M., Foong, J.P.P., and Bornstein, J.C. (2017). Cholera Toxin Induces Sustained Hyperexcitability in Myenteric, but Not Submucosal, AH Neurons in Guinea Pig Jejunum. Frontiers in Physiology. 254 (8). Chambers, J.D., Bornstein, J.C., Gwynne, R.M., Koussoulas, K., and Thomas, E.A. (2014). A detailed, conductance-based computer model of intrinsic sensory neurons of the gastrointestinal tract. Am J Physiol 307(5) G517-G532. Abstracts (* refereed): Koussoulas, K., Gwynne, R.M., Foong, J.P.P., Ross, C., Savidge, T.C., and Bornstein, J.C. Clostridium difficile toxin and microbial-derived GABA signals converge to hyperexcite myenteric intrinsic sensory neurons (2015). Gastroenterology 148, S-21* Dann, S.M.,
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