title: Agonist-evoked Ca2+signaling in enteric glia drives neural programs that regulate intestinal motility in mice.
abstract: OBJECTIVE
  Gastrointestinal motility is regulated by enteric neural circuitry that includes enteric neurons and glia. Enteric glia monitor synaptic activity and exhibit responses to neurotransmitters that are encoded by intracellular calcium (Ca2+) signaling. What role evoked glial responses play in the neural regulation of gut motility is unknown. We tested how evoking Ca2+signaling in enteric glia affects the neural control of intestinal motility.
  
  
  METHODS
  We used a novel chemogenetic mouse model that expresses the designer receptor hM3Dq under the transcriptional control of the glial fibrillary acidic protein (GFAP) promoter (GFAP::hM3Dqmice) to selectively trigger glial Ca2+signaling. We usedin situCa2+imaging and immunohistochemistry to validate this model and assessed gut motility by measuring pellet output and composition, colonic bead expulsion time, small intestinal transit time, total gut transit time, colonic migrating motor complex (CMMC) recordings and muscle tension recordings.
  
  
  RESULTS
  hM3Dq receptor expression is confined to GFAP-positive enteric glia in the intestines ofGFAP::hM3Dqmice. In these mice, application of the hM3Dq agonist clozapine-N-oxide (CNO) selectively triggers intracellular Ca2+responses in enteric glia. Glial activation drove neurogenic contractions in the ileum and colon but had no effect on neurogenic relaxations. CNO enhanced the amplitude and frequency of CMMCs inex vivopreparations of the colon and CNO increased colonic motilityin vivo.CNO had no effect on the composition of fecal matter, small intestinal transit or whole gut transit.
  
  
  CONCLUSIONS
  Glial excitability encoded by intracellular Ca2+signaling functions to modulate excitatory enteric circuits. Selectively triggering glial Ca2+signaling might be a novel strategy to improve gut function in motility disorders.
authors.affiliation: Department of Physiology, Michigan State University, 567 Wilson Road, East Lansing, MI, 48824 USA.
authors.forename: Jonathon L
authors.initials: JL
authors.lastname: McClain
authors.affiliation: Department of Physiology, Michigan State University, 567 Wilson Road, East Lansing, MI, 48824 USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Fried
authors.affiliation: Department of Physiology, Michigan State University, 567 Wilson Road, East Lansing, MI, 48824 USA ; Neuroscience Program, Michigan State University, 567 Wilson Road, East Lansing, MI, 48824 USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Gulbransen
keywords: autonomic; chemogenetic; enteric nervous system; gut; intestine