The Enteric Nervous System, Plasticity and Survival

Abstract: The thesis deals with plasticity in terms of neurotransmitter expression and survival of neurons in the adult enteric nervous system (ENS). Several motility disorders have been suggested to originate in developmental defects, neurodegeneration, or insufficient innervation by the ENS. Normal distribution of the interstitial cells of Cajal (ICC), found in close relationship to enteric neurons, is also likely to be essential for gut motility. A number of factors governing development of the ENS have been identified. Our knowledge of factors important for maintenance, adaptation, and survival of the adult ENS is, however, still poor. In Papers I-III, the ENS and ICC were studied in the lethal spotted (ls)-mice; an experimental model for congenital aganglionosis. In Paper IV, two models for primary culturing of myenteric neurons were established and evaluated. In Papers V and VI, survival of myenteric neurons and possible neurotrophic effects of vasoactive intestinal peptide (VIP), nitric oxide (NO), and pituitary adenylate cyclase-activating peptide (PACAP) were investigated in cultures of dissociated myenteric neurons from rat small intestine. The rectum of ls-mice showed an absence of both myenteric and submucous nerve cell bodies, and also a reduction of nerve fibers immunoreactive for neuronal nitric oxide synthase (NOS) and various neuropeptides; similar to the condition in human Hirschsprung’s disease. In addition, abnormalities in the total number of neurons, the relative frequency of neurons expressing various neurotransmitters, and also the relative frequency of ICC in the ganglionic intestine in homozygous ls-mice (congenital aganglionosis of the rectum) were demonstrated. The feasibility of enteric neuronal tissue autotransplantation in the ls-mice in terms of neuronal survival was shown. By utilization of primary cell cultures it was demonstrated that VIP and NO promote survival of myenteric neurons. In contrast, no difference in survival was found after culturing in the presence of PACAP-38 or PACAP-27. Neurons expressing VIP and/or NOS increased in number during culture, whereas no change in the number of PACAP-containing neurons could be detected.