title: Enhanced serotonin signaling increases intestinal neuroplasticity.
abstract: The intestinal mucosa recovers from injury by accelerating enterocyte proliferation resulting in villus growth. A similar phenomenon is seen after massive bowel resection. Serotonin (5-HT) has been implicated as an important regulator of mucosal homeostasis by promoting growth in the epithelium. The impact of 5-HT on other components of growing villi is not known. We hypothesized that 5-HT-stimulated growth in the intestinal epithelium would be associated with growth in other components of the villus such as enteric neural axonal processes.
  
  
  
  Enteric serotonergic signaling is inactivated by the serotonin reuptake transporter, or SERT, molecule. Enhanced serotonin signaling was achieved via SERT knockout (SERTKO) and administration of selective serotonin reuptake inhibitors (SSRI) to wild-type mice (WT-SSRI). 5-HT synthesis inhibition was achieved with administration of 4-chloro-L-phenylalanine (PCPA). Intestinal segments from age-matched WT, SERTKO, WT-SSRI, and corresponding PCPA-treated animals were assessed via villus height, crypt depth, and crypt proliferation. Gap 43, a marker of neuroplasticity, was assessed via immunofluorescence and Western blot.
  
  
  
  SERTKO and WT-SSRI mice had taller villi, deeper crypts, and increased enterocyte proliferation compared with WT mice. Gap 43 expression via immunofluorescence was significantly increased in SERTKO and WT-SSRI samples, as well as in Western blot analysis. PCPA-treated SERTKO and WT-SSRI animals demonstrated reversal of 5-HT-induced growth and Gap 43 expression.
  
  
  
  Enhanced 5-HT signaling results in intestinal mucosal growth in both the epithelial cell compartment and the enteric nervous system. Furthermore, 5-HT synthesis inhibition resulted in reversal of effects, suggesting that 5-HT is a critically important regulator of intestinal mucosal growth and neuronal plasticity.
authors.affiliation: Section of Pediatric Surgery, Department of Surgery, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Chasen J
authors.initials: CJ
authors.lastname: Greig
authors.affiliation: Section of Pediatric Surgery, Department of Surgery, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Neeru
authors.initials: N
authors.lastname: Gandotra
authors.affiliation: Section of Pediatric Surgery, Department of Surgery, Yale School of Medicine, New Haven, Connecticut.
authors.forename: John J
authors.initials: JJ
authors.lastname: Tackett
authors.affiliation: Section of Pediatric Surgery, Department of Surgery, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Michaela C
authors.initials: MC
authors.lastname: Bamdad
authors.affiliation: Section of Pediatric Surgery, Department of Surgery, Yale School of Medicine, New Haven, Connecticut. Electronic address: robert.cowles@yale.edu.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cowles
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D017615:Enteric Nervous System / Q000254:growth & development* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D019922:GAP-43 Protein / Q000378:metabolism; D007413:Intestinal Mucosa / Q000254:growth & development* / Q000294:innervation / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D019922:GAP-43 Protein; D012701:Serotonin
keywords: Mouse model; Neuroplasticity; Proliferation; Serotonin signaling; Small intestine