Serotonin Signaling in the Neural Development and Function of the Lower Urinary Tract

Abstract

The autonomic and sensory nervous systems are derived from the neural crest and are required for the normal functioning of visceral organ systems, including the bladder and urethra (lower urinary tract, LUT). Surprisingly little is known about the molecular factors involved in the normal development and maturation of LUT innervation. Serotonin receptor 5-HT3A (encoded by gene Htr3a) was found to be significantly enriched in differentiating autonomic neurons innervating the LUT. A variety of pharmacological, physiological, and behavioral approaches were used to determine the roles of 5-HT3A in the development of LUT innervation. Over-stimulating 5-HT3A in sacral neural crest cells in vitro disrupted neuronal differentiation outcomes and inhibited neurite outgrowth in pelvic ganglia explants. Loss of 5-HT3A in vivo resulted in a transient disturbance of PG autonomic neuronal subtypes and an increase in autonomic and sensory neuronal fibers innervating the bladder. Male Htr3a knockout mice exhibited increased urinary voiding frequency and decreased bladder voiding efficiency. Overall, the work presented in this dissertation highlights a previously unknown role for 5-HT3A signaling in peripheral nervous system development and its requirement for normal adult urinary tract function.