Responses to Enteric Motor Neurons in the Gastric Fundus of Mice With Reduced Intramuscular Interstitial Cells of Cajal

BACKGROUND/AIMS: Interstitial cells of Cajal (ICC) play important functions in motor activity of the gastrointestinal tract. The role of ICC as pacemakers is well established, however their participation in neurotransmission is controversial. Studies using mutant animals that lack ICC have yielded variable conclusions on their importance in enteric motor responses. The purpose of this study was to: (1) clarify the role of intramuscular ICC (ICC-IM) in gastric motor-neurotransmission and (2) evaluate remodeling of enteric motor responses in W/W(V) mice. METHODS: Kit immunohistochemistry and post-junctional contractile responses were performed on fundus muscles from wild-type and W/W(V) mice and quantitative polymerase chain reaction (qPCR) was used to evaluate differences in muscarinic and neurokinin receptor expression. RESULTS: Although ICC-IM were greatly reduced in comparison with wild-type mice, we found that ICC-IM persisted in the fundus of many W/W(V) animals. ICC-IM were not observed in W/W(V) group 1 (46%) but were observed in W/W(V) group 2 (40%). Evoked neural responses consisted of excitatory and inhibitory components. The inhibitory component (nitrergic) was absent in W/W(V) group 1 and reduced in W/W(V) group 2. Enhanced excitatory responses (cholinergic) were observed in both W/W(V) groups and qPCR revealed that muscarinic-M3 receptor expression was significantly augmented in the W/W(V) fundus compared to wild-type controls. CONCLUSIONS: This study demonstrates that ICC-IM mediate nitrergic inhibitory neurotransmission in the fundus and provides evidence of plasticity changes in neuronal responses that may explain discrepancies in previous functional studies which utilized mutant animals to examine the role of ICC-IM in gastric enteric motor responses.

Ionic Conductance(s) in Response to Post-junctional Potentials

The gastrointestinal motility is regulated by extrinsic and intrinsic neural regulation. Intrinsic neural pathways are controlled by sensory input, inter-neuronal relay and motor output. Enteric motor neurons release many transmitters which affect post-junctional responses. Post-junctional responses can be excitatory and inhibitory depending on neurotransmitters. Excitatory neurotransmitters induce depolarization and contraction. In contrast, inhibitory neurotransmitters hyperpolarize and relaxe the gastrointestinal smooth muscle. Smooth muscle syncytium is composed of smooth muscle cells, interstitial cells of Cajal and platelet-derived growth factor receptor alpha-positive (PDGFRalpha+) cells (SIP syncytium). Specific expression of receptors and ion channels in these cells can be affected by neurotransmitters. In recent years, molecular reporter expression techniques are able to study the properties of ion channels and receptors in isolated specialized cells. In this review, we will discuss the mechanisms of ion channels to interpret the post-junctional responses in the gastrointestinal smooth muscles.