Department of Neurological Sciences

Gary M. Mawe, PhD 
Professor, Department of Neurological Sciences 

Lab Research

CONTRIBUTIONS TO SCIENCE

Intestinal Serotonin Signaling

The majority of the serotonin (5-HT) in the body is synthesized and released by enterochromaffin cells in the mucosa of the GI tract.  There, it acts as an important signaling molecule to activate GI reflexes and to send physiological and pathophysiological signals to the CNS.  During my postdoctoral studies under the direction of Dr. Michael Gershon, we made the novel discovery that enteric neurons express more than one type of 5-HT receptor.  At the University of Vermont, my colleagues and I have investigated changes in serotonin signaling that occur in animal models of intestinal inflammation, and we have studied the distribution and functions of 5-HT receptors that are targeted in therapies for irritable bowel syndrome (IBS).  For example, we have shown in a number of animal models that the serotonin selective reuptake transporter (SERT), which terminates serotonin signaling, is down-regulated in colitis. We subsequently found that, of many pro-inflammatory molecules tested, IFN-γ and TNF-α, decrease SERT expression and function in intestinal epithelial cells, and that SERT expression is differentially regulated in intestinal epithelial cells as compared to neurons.  We have also demonstrated that 5-HT4 receptors are extensively expressed in the colonic mucosa, and that their activation promotes motility and suppresses visceral hypersensitivity.  This could be of clinically applicable because 5-HT4 agonists have been shown to have benefit for IBS with constipation and chronic constipation.  Mucosal 5-HT4 receptors could provide a safe and effective target for this class of drugs that has been plagued with cardiovascular side effects.  Most recently, we have discovered that luminal administration of 5-HT4 agonists accelerates recovery from colitis, and that inhibition or deletion of this receptor leads to a low level inflammatory state in the colon.  These results indicate that 5-HT4 receptors are important for epithelial homeostasis.

Linden, D.R., J.-X. Chen, M.D. Gershon, K.A. Sharkey and G.M. Mawe (2003) Serotonin availability is increased in mucosa of guinea pigs with TNBS-induced colitis. American Journal of Physiology  285: G207-G216.  PMID: 12646422

Foley, K.F., C. Pantano, A. Ciolino and G.M. Mawe (2007) IFN-γ and TNF-α decrease serotonin transporter function and expression in intestinal epithelial cells. American Journal of Physiology292:G779-G784. PMID:   17170025

Hoffman, J.M., K. Tyler, S.J. MacEachern, O.B. Balemba, A.C. Johnson, E.M. Brooks, H. Zhao, G.M. Swain, P.L. Moses, J.J. Galligan, K.A. Sharkey, B. Greenwood-Van Meerveld and G.M. Mawe (2012) Activation of colonic mucosal 5-HT₄ receptors enhances propulsive motility and inhibits visceral hypersensitivity.  Gastroenterology  142:844-854. PMID:  22226658

Spohn, S.N., F. Bianco, R.B. Scott, C.M. Keenan, C.H. O'Neill, E. Bonora, M. Dicay, B. Lavoie, R.L. Wilcox, W.K. MacNaughton, R. De Giorgio, K.A. Sharkey, G.M. Mawe  (2016) Protective actions of epithelial 5-HT₄ receptors in normal and inflamed colon. Gastroenterology  151:933-944

Inflammation-induced Neuroplasticity

The existence of intrinsic reflex circuits in the intestines has been appreciated since the late 1890s when Bayliss and Starling established the Law of the Intestine, but it was not until a century later that we were able to identify the various neuronal elements of these circuits.  Since then, my lab and the lab of Dr. Keith Sharkey, my colleague at the University of Calgary, have collaborated to systematically evaluate the reflex circuits in the intestines to determine what changes occur in response to inflammation, which of these changes persist beyond recovery of inflammation (which has implications for IBS), and what neuroplastic alterations contribute to inflammation-induced changes in gut function.  We have shown that intrinsic sensory neurons are hyperexcitable, that interneuronal synaptic communication is augmented, and that purinergic neuromuscular communication is blunted in colitis.  We have also shown that these changes contribute to disrupted propulsive motility, and that the changes in sensory neuron function and interneuronal synaptic strength persist well beyond recovery from inflammation, but that purinergic transmission is rapidly restored.  This makes sense, because we recently demonstrated that purinergic neuromuscular transmission is decreased because oxidative stress disrupts purine synthesis in the mitochondria. An important discovery we made conducting these studies is that activation of enteric glia contributes to neuronal cell death in the colon.

Linden, D.R., K.A. Sharkey and G.M. Mawe (2003) Enhanced excitability of myenteric AH neurones in the inflamed guinea pig distal colon.  TheJournal of Physiology 547: 589-601.  PMID: 12562910

Krauter, E.C. D.R. Linden, K.A. Sharkey and G.M. Mawe (2007) Synaptic plasticity in guinea pig myenteric neurons: Presynaptic mechanisms of inflammation-induced synaptic facilitation.  TheJournal of Physiology 581:787-800. PMID: 17363386

Strong, D.S., C.F. Cornbrooks, J.A. Roberts, J.M. Hoffman, K.A. Sharkey, G.M. Mawe (2010) Purinergic neuromuscular transmission is selectively attenuated in ulcerated regions of inflamed guinea pig distal colon.  Journal of Physiology (London)  588: 847–859.  PMID: 20064853

Gulbransen, M. Bashashati, S.A. Hirota, J.A. Roberts, P.L. Beck, J.A. MacDonald, D.A. Muruve, D.M. McKay, G.M. Mawe, R.J. Thompson, and K.A. Sharkey (2012) Activation of neuronal P2X₇ receptor-Pannexin-1 mediates death of enteric neurons during colitis. Nature Medicine 18: 600-604.  PMID: 22426419

Translational Investigations of human GI motility and Inflammatory Disorders

As a basic scientist at The University of Vermont, I have been fortunate to enjoy a high level of cooperation from, and collaboration with, clinicians in Gastroenterology, Colorectal Surgery, and Pathology. These interactions have provided extensive access to human specimens and input from these clinicians has helped focus our studies on clinically relevant goals.  In some cases, our animal model studies have led to hypotheses that we tested in human populations, and in other cases, our findings in human specimens have led to mechanistic studies involving animals and/or cell lines.  We have determined the electrical, synaptic and neurochemical properties of human gallbladder neurons.  We also demonstrated that the blood of achalasia patients contains anti-enteric neuron antibodies, supporting the concept that achalasia is an autoimmune disorder that involves inflammation of lower esophageal sphincter ganglia and associated neuronal loss.  Our most extensive work involving human specimens has been related to mucosal serotonin signaling in various gastrointestinal disorders.  We were the first to discover a molecular alteration in the intestines of individuals with IBS when we reported that SERT expression is decreased IBS, as well as ulcerative colitis.  We have studied a number of other disorders, including chronic constipation and diverticulosis/itis, and we have shown that children with IBS also exhibit decreased mucosal SERT.  The various changes in serotonin signaling that we have reported in these disorders likely contribute to altered colonic function and sensation.

Moses, P.L., L.M. Ellis, M.R. Anees, R.I. Rothstein, K.M. Wood, M.C. Moses J.B. Meddings, W. Ho, K.A. Sharkey and G.M. Mawe (2003) Anti-Neuronal Antibodies in Idiopathic Achalasia and Gastroesophageal Reflux Disease.  Gut 52:629-636. PMID: 12692044

Coates MD, CR Mahoney, DR Linden, JE Sampson, J Chen, H Blaszyk, MD Crowell, KA Sharkey, MD Gershon, GM Mawe*, PL Moses* (2004) Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and IBS.  Gastroenterology 126:1657-1664. * indicates co-senior authors. PMID: 15188158

Faure, C., N. Patey, C. Gauthier, E.M. Brooks, G.M. Mawe (2010) Serotonin Signaling Is Altered in Irritable Bowel Syndrome With Diarrhea but Not in Functional Dyspepsia in Pediatric Age Patients. Gastroenterology 139:249-258.  PMID: 20303355

Costedio, M.M., M.D. Coates, E.M. Brooks, Lisa M. Glass, Eric K. Ganguly, H.J. Blaszyk, A.L. Ciolino, M.J. Wood, D. Strader, N.H. Hyman, P.L. Moses, and G.M. Mawe (2010) Mucosal serotonin signaling is altered in chronic constipation, but not in opiate-induced constipation.  American Journal of Gastroenterology 105: 1173-80.  PMID: 20010921