Author: Mohammad Mustafa Ahmadzai

Publisher:

Published: 2020

Total Pages: 128

ISBN-13:

Motility is an essential feature of gastrointestinal (GI) physiology that is necessary for life. Defects in motility are seen in a spectrum of GI diseases including functional GI disorders (FGIDs), which are prevalent throughout the world and are associated with reduced quality of life. FGIDs remain a substantial social burden that continues to exact tremendous personal and economic costs. Effective treatments for FGIDs are currently lacking due, in part, to an incomplete understanding of the mechanisms regulating GI motility.The motility of the GI tract is controlled by the enteric nervous system (ENS) through neural circuits embedded within the gut wall. Enteric neurons serve effector and regulatory functions and are subject to dynamic and reciprocal input from surrounding populations of enteric glia. Enteric glia are specialized peripheral glial cells that sense neural circuit activity through neurotransmitter receptors and reciprocally modify their function through gliotransmitter release. While interactions between neurons and glia of the central nervous system (CNS) are remarkably synapse-specific, whether this sophisticated degree of neurocircuit modulation occurs in the ENS has never been explored. The overarching objective of this dissertation was to characterize the mechanisms by which enteric glia modulate activity within enteric motor circuits and to elucidate the role of enteric glia in the pathogenesis of FGIDs.In the first part of this dissertation, we developed a novel mouse model that combined chemogenetics and optogenetics to characterize network-level activity in ENS motor circuits. We report here the first evidence that enteric glia are functionally committed to specific circuit pathways of the ENS. In the second part of this dissertation, we combine Ca2+ imaging, genetic, immunohistochemistry, ex vivo and in vivo motility techniques to demonstrate a novel role the type I lysophosphatidic acid receptor (LPAR1) in the regulation of GI motility by enteric glia. Our study reveals a striking reduction in glial LPAR1 expression in chronic intestinal pseudo-obstruction (CIPO), a severe FGID in which failure in GI motility leads to life-threatening episodes of bowel obstruction. Together, our studies shed new light on the mechanisms by which enteric glia regulate ENS motor activity under physiological conditions and how dysregulations in glial signaling can drive GI dysmotilities like CIPO.