Agonist-Evoked Ca2+ Signaling in Enteric Glia Drives Neural Programs That Regulate Intestinal Motility in Mice

Background & Aims 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::hM3Dq mice) to selectively trigger glial Ca2+ signaling. We used in situ Ca2+ imaging and immunohistochemistry to validate this model, and we 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 Expression of the hM3Dq receptor is confined to GFAP-positive enteric glia in the intestines of GFAP::hM3Dq mice. 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 in ex vivo preparations of the colon, and CNO increased colonic motility in 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.

• Publication year

  2015

• Venue

  Cellular and Molecular Gastroenterology and Hepatology

• Publication date

  2015-08-22

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.jcmgh.2015.08.004PMID 26693173PMCID 4673674
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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