Physiology - Research Publications
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ItemEndogenous Glutamate Excites Myenteric Calbindin Neurons by Activating Group I Metabotropic Glutamate Receptors in the Mouse Colon(FRONTIERS MEDIA SA, 2019-05-01)Glutamate is a classic excitatory neurotransmitter in the central nervous system (CNS), but despite several studies reporting the expression of glutamate together with its various receptors and transporters within the enteric nervous system (ENS), its role in the gut remains elusive. In this study, we characterized the expression of the vesicular glutamate transporter, vGluT2, and examined the function of glutamate in the myenteric plexus of the distal colon by employing calcium (Ca2+)-imaging on Wnt1-Cre; R26R-GCaMP3 mice which express a genetically encoded fluorescent Ca2+ indicator in all enteric neurons and glia. Most vGluT2 labeled varicosities contained the synaptic vesicle release protein, synaptophysin, but not vesicular acetylcholine transporter, vAChT, which labels vesicles containing acetylcholine, the primary excitatory neurotransmitter in the ENS. The somata of all calbindin (calb) immunoreactive neurons examined received close contacts from vGluT2 varicosities, which were more numerous than those contacting nitrergic neurons. Exogenous application of L-glutamic acid (L-Glu) and N-methyl-D-aspartate (NMDA) transiently increased the intracellular Ca2+ concentration [Ca2+]i in about 25% of myenteric neurons. Most L-Glu responsive neurons were calb immunoreactive. Blockade of NMDA receptors with APV significantly reduced the number of neurons responsive to L-Glu and NMDA, thus showing functional expression of NMDA receptors on enteric neurons. However, APV resistant responses to L-Glu and NMDA suggest that other glutamate receptors were present. APV did not affect [Ca2+]i transients evoked by electrical stimulation of interganglionic nerve fiber tracts, which suggests that NMDA receptors are not involved in synaptic transmission. The group I metabotropic glutamate receptor (mGluR) antagonist, PHCCC, significantly reduced the amplitude of [Ca2+]i transients evoked by a 20 pulse (20 Hz) train of electrical stimuli in L-Glu responsive neurons. This stimulus is known to induce slow synaptic depolarizations. Further, some neurons that had PHCCC sensitive [Ca2+]i transients were calb immunoreactive and received vGluT2 varicosities. Overall, we conclude that electrically evoked release of endogenous glutamate mediates slow synaptic transmission via activation of group I mGluRs expressed by myenteric neurons, particularly those immunoreactive for calb.
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ItemSpatiotemporal Mapping Reveals Regional Gastrointestinal Dysfunction in mdx Dystrophic Mice Ameliorated by Oral L-arginine Supplementation(KOREAN SOC NEUROGASTROENTEROLOGY & MOTILITY, 2020-01)BACKGROUND/AIMS: Patients with Duchenne muscular dystrophy exhibit significant, ongoing impairments in gastrointestinal (GI) function likely resulting from dysregulated nitric oxide production. Compounds increasing neuronal nitric oxide synthase expression and/or activity could improve GI dysfunction and enhance quality of life for dystrophic patients. We used video imaging and spatiotemporal mapping to identify GI dysfunction in mdx dystrophic mice and determine whether dietary intervention to enhance nitric oxide could alleviate aberrant colonic activity in muscular dystrophy. METHODS: Four-week-old male C57BL/10 and mdx mice received a specialized diet either with no supplementation (control) or supplemented (1 g/kg/day) with L-alanine, L-arginine, or L-citrulline for 8 weeks. At the conclusion of treatment, mice were sacrificed by cervical dislocation and colon motility examined by spatiotemporal (ST) mapping ex vivo. RESULTS: ST mapping identified increased contraction number in the mid and distal colon of mdx mice on control and L-alanine supplemented diets relative to C57BL/10 mice (P < 0.05). Administration of either L-arginine or L-citrulline attenuated contraction number in distal colons of mdx mice relative to C57BL/10 mice. CONCLUSIONS: GI dysfunction in Duchenne muscular dystrophy has been sadly neglected as an issue affecting quality of life. ST mapping identified regional GI dysfunction in the mdx dystrophic mouse. Dietary interventions to increase nitric oxide signaling in the GI tract reduced the number of colonic contractions and alleviated colonic constriction at rest. These findings in mdx mice reveal that L-arginine can improve colonic motility and has potential therapeutic relevance for alleviating GI discomfort, improving clinical care, and enhancing quality of life in Duchenne muscular dystrophy.
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ItemThe Role of the Gastrointestinal Mucus System in Intestinal Homeostasis: Implications for Neurological Disorders(FRONTIERS MEDIA SA, 2020-05-28)Mucus is integral to gut health and its properties may be affected in neurological disease. Mucus comprises a hydrated network of polymers including glycosylated mucin proteins. We propose that factors that influence the nervous system may also affect the volume, viscosity, porosity of mucus composition and subsequently, gastrointestinal (GI) microbial populations. The gut has its own intrinsic neuronal network, the enteric nervous system, which extends the length of the GI tract and innervates the mucosal epithelium. The ENS regulates gut function including mucus secretion and renewal. Both dysbiosis and gut dysfunction are commonly reported in several neurological disorders such as Parkinson's and Alzheimer's disease as well in patients with neurodevelopmental disorders including autism. Since some microbes use mucus as a prominent energy source, changes in mucus properties could alter, and even exacerbate, dysbiosis-related gut symptoms in neurological disorders. This review summarizes existing knowledge of the structure and function of the mucus of the GI tract and highlights areas to be addressed in future research to better understand how intestinal homeostasis is impacted in neurological disorders.