Cholinergic systems: Human diseases, animal models, and prospects for therapy

Cholinergic neurons, including those in the basal forebrain, brainstem, and spinal cord, play critical roles in the functions of a variety of neural circuits, and abnormalities of these neuronal populations are responsible for the clinical manifestations of several human neurological disorders. In Alzheimer's disease (AD), basal forebrain cholinergic neurons are among the vulnerable populations of neurons. In individuals with amyotrophic lateral sclerosis (ALS), large motor neurons of the brainstem and spinal cord degenerate, whereas patients with multiple system atrophy (Shy-Drager syndrome) show lesions of cholinergic cells in Onufrowicz's (Onuf's) nucleus and the intermediolateral cell column of the spinal cord. In each of these illnesses, the dysfunction and death of these neurons are linked to the clinical phenotypes of disease— that is, impairments in attention, learning, and memory in AD, weakness in ALS, and impotence, incontinence and orthostatic hypertension in Shy-Drager syndrome. Recent studies suggest that different populations of cholinergic neurons may respond to different trophic factors, raising the possibility that, in the future, trophic factors may be used to preserve the functions and promote the survival of these subsets of nerve cells. This chapter outlines the current understanding of the involvement of these cholinergic systems in several human diseases and their respective animal models, and suggests directions of research that may lead to future trophic factor therapeutic approaches to restore the functions of these systems.