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Received April 5, 2002
Accepted after revision June 24, 2002
1 Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA
2 Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA
* To whom correspondence should be addressed. E-mail: sean{at}physio.unr.edu.
Studies of W/WV mice, which lack intramuscular interstitial cells of Cajal (IC-IMs), have suggested that IC-IMs act as mediators of enteric motor neurotransmission in the gastrointestinal tract. We have studied Sl/Sld mice, which lack the ability to make membrane-bound stem cell factor, to determine the consequences of inappropriate stem cell factor expression on IC-IM populations and on enteric motor neurotransmission. IC-IMs were found within the circular and longitudinal muscles of the gastric fundus of wild-type mice. IC-IMs were intimately associated with motor nerve terminals and nerve varicosities formed synaptic structures with these cells. IC-IMs were also connected with neighbouring smooth muscle cells via gap junctions. Immunohistochemistry and electron microscopy showed that IC-IMs were absent from fundus muscles of Sl/Sld mice, but the density of excitatory and inhibitory nerves was not significantly different than in wild-type muscles. Loss of IC-IMs was associated with decreased membrane noise (unitary potentials) and significant reductions in post-junctional excitatory and inhibitory enteric nerve responses. Reductions in neural responses were not due to defects in smooth muscle cells as responses to exogenous ACh and K+-induced depolarization were normal in Sl/Sld mice. Responses to neurally released ACh were revealed in Sl/Sld mice by inhibiting ACh breakdown with the acetylcholinesterase inhibitor neostigmine. Inhibitory nerve stimulation elicited inhibitory junction potentials (IJPs) and relaxations in wild-type mice. IJPs were reduced in amplitude and relaxation responses were absent in Sl/Sld mice. These observations suggest that membrane-bound stem cell factor is essential for development of IC-IMs and that the close, synaptic-like relationship between nerve terminals and IC-IMs may be the primary site of innervation by enteric motor neurons in gastric muscles.
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