Gastrointestinal (GI) motility dysfunction is a debilitating feature that presents asa symptom in a number of conditions. These include primary GI disorders likeinflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) but alsosecondary conditions like diabetes mellitus, Parkinson's Disease and simply as aconsequence of physiological aging. Although as many as 1 in 4 persons worldwide areaffected by GI motility dysfunction, there is a significant lack of safe and effective drugs,due to a gap in the knowledge regarding the cellular mechanisms that contribute to GImotility dysfunction.Normal gut function is controlled by the enteric nervous system (ENS), anintrinsic neuronal network comprised of enteric neurons and supporting glial cells, whichis embedded within the walls of the GI tract. Death of enteric neurons, and the resultingdisruption of this neuronal network, contributes to motility dysfunction duringinflammation. In this dissertation, we investigate how increased oxidative stress andimbalanced immune homeostasis, key factors associated with GI inflammation,contribute to enteric neuropathy. We hypothesize a role for enteric glial cells, which arecapable of modulating ENS oxidative stress, and also have an importantimmunomodulatory role in the ENS.The work in this dissertation used a combination of transgenic animal strains,immunohistochemistry (IHC), pharmacological modulators, Ca2+ imaging and in situ andin vivo models of colitis to investigate our hypothesis. We show a key role for entericglial regulation of oxidative stress in mediating neuronal loss. During inflammation,purinergic activation of enteric glia drives enteric neuron death through a pathway thatrequires glial nitric oxide (NO) production and glial Cx43 hemichannels anddemonstrates a novel pathogenic role for enteric glia. Further, glial production of theantioxidant reduced glutathione (GSH) is necessary for neuronal survival in situ,although whole body GSH depletion has novel protective roles against key features ofmurine colitis. Mice with disrupted in T cell signaling of the anti-inflammatory cytokineTGFβ had altered GI function, immune homeostasis and glial activation at the level ofthe myenteric plexus. Lastly, we show that key pro-inflammatory mediators differentiallyalter glial Cx43 channel opening in quiescent versus activated enteric glia.Our data provide new evidence for an active role for enteric glial cells in GI(patho)physiology. Specifically, we demonstrate that enteric glia are involved inmediating the effects of oxidative stress and immune imbalance during GI inflammationand propose novel targets for the development of improved therapeutics to treat GImotility dysfunction.
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