Lack of serotonin 5-HT_2B receptor alters proliferation and network volume of interstitial cells of Cajal in vivo

Background Normal gastrointestinal motility requires intact networks of interstitial cells of Cajal (ICC). Interstitial cells of Cajal numbers are maintained by a balance between cell loss factors and survival/trophic/growth factors. Activation of 5-HT_2B receptors expressed on ICC increases ICC proliferation in vitro. It is not known whether 5-HT_2B receptors on ICC are activated in vivo. The aims of this study were to investigate if adult ICC proliferate, whether the proliferation of ICC in vivo is affected by knocking out the 5-HT_2B receptor, and if alterations in proliferation affect ICC networks. Methods Proliferating ICC were identified by immunoreactivity for Ki67 in both the myenteric and deep muscular plexus regions of the jejunum in mice with a targeted insertion of a neomycin resistance cassette into the second coding exon of the htr2b receptor gene. Key Results Adult ICC do proliferate. The number of proliferating ICC was lower in the myenteric plexus region of Htr2b^-/- compared to Htr2b^+/+ mice. The volume of Kit-positive ICC was 30% lower in the myenteric plexus region and 40% lower in the deep muscular plexus region in Htr2b^-/- mice where the number of ICC was also reduced. Conclusions & Inferences Interstitial cells of Cajal proliferate in adult mice and activation of 5-HT_2B receptors results in increased proliferation of ICC in vivo. Furthermore, lack of 5-HT_2B receptor signaling reduces the density of ICC networks in mature mice. These data suggest that 5-HT_2B receptor signaling is required for maintenance of ICC networks, adding 5-HT to the growing number of factors shown to regulate ICC networks.