Consequences and mechanisms of sympathetic axon degeneration

Visceral target cells enjoy intimate relationships with autonomic axons. Much attention has been devoted to understanding how this innervation is established in development and maintained in maturity. However, targets are often deprived of innervation. This may occur as a result of pathological events such as trauma or neuropathy, but can also occur as a result of normal physiological processes. For example, ‘physiological denervation’ is a normal feature of the sympathetic innervation of the female reproductive tract including the uterus and vagina. We now know that this occurs as a result of both withdrawal of growth-promoting factors and upregulation of genes and proteins that induce sympathetic axon degeneration. In this context, pruning of sympathetic axon terminals appears to be an important adaptive mechanism promoting fertility and parturition. However, deprivation of sympathetic innervation is not without additional consequences. Sympathetic denervation directly impacts target cells by altering cell size, proliferative state, receptor sensitivity, gene expression, phenotype and functional properties. Moreover, heterologous axonal populations present within the ground plexus of targets including orbital smooth muscle are also affected. Impact on co-projecting residual axons can include changes in neurotransmitter and trophic phenotypes, proliferation through axon sprouting, and in some cases changes from inhibitory to excitatory functional properties. Collectively, these findings imply a dynamic relationship between innervation and target cells under normal physiological conditions, whereby target cells may choose to undergo selective denervation, with significant potential consequences for both the target cell and its remaining innervation.