Serotonin Receptor 5-HT3A Affects Development of Bladder Innervation and Urinary Bladder Function.

K Elaine Ritter,Dale E Bjorling,Chad M Vezina,Zunyi Wang,E Michelle Southard-Smith

doi:10.3389/fnins.2017.00690

Abstract

The autonomic and sensory nervous systems are required for proper function of all visceral organs, including the lower urinary tract (LUT). Despite the wide prevalence of bladder dysfunction, effective treatment options remain limited. Pelvic innervation regenerative strategies are promising, but surprisingly little is known about the molecular factors driving the development of bladder innervation. Given prior evidence that serotonin receptor 5-HT3A is expressed early in LUT development and is an important mediator of adult bladder function, we sought to determine if 5-HT3A is required for the development of autonomic innervation of the bladder. We found that 5-HT3A is expressed early in fetal mouse pelvic ganglia and is maintained through adulthood. Htr3a knockout male mice, but not females, exhibit increased urinary voiding frequency compared to wild type littermates. Analysis of LUT function via anesthetized cystometry revealed decreased voiding efficiency in male Htr3a mutants. Htr3a−/− mutant animals exhibit a transient disturbance of autonomic neuronal subtype markers (tyrosine hydroxylase and choline acetyl transferase) within the fetal pelvic ganglia, although the imbalance of neuronal subtype markers assayed is no longer apparent in adulthood. Loss of 5-HT3A activity results in a higher density of autonomic and sensory neuronal fibers supplying bladder smooth muscle in both fetal and adult mice. Collectively, our findings highlight 5-HT3A as a critical component in the autonomic control of micturition and identify a novel role for this serotonin receptor in peripheral nervous system development.

Highlights

The lower urinary tract (LUT, bladder and urethra) is responsible for the storage and timely elimination of urine and is controlled by autonomic, sensory, and central motor innervation
From these experiments we conclude that serotonin receptor 5-HT3A is expressed early in developing autonomic LUT innervation, and its expression is maintained in many pelvic ganglia neurons through sexual maturity in adult mice
While the effects of serotonin signaling in neural development have been studied for decades, the 5-HT3A serotonin receptor has only recently been recognized as a key player in developmental mechanisms (Engel et al, 2013)

Summary

Introduction

The lower urinary tract (LUT, bladder and urethra) is responsible for the storage and timely elimination of urine and is controlled by autonomic, sensory, and central motor innervation. The autonomic components are comprised of the pelvic ganglia (PG), which harbor both sympathetic and parasympathetic neurons (Wanigasekara et al, 2003). The coordination of these neural components allows the bladder smooth muscle to relax as it fills with urine while the internal. Htr3a in Development of Bladder Function urethral sphincter contracts to prevent urine leakage, and vice versa when the micturition reflex is initiated (de Groat et al, 2015). When any of these neural components do not function properly, urinary incontinence or retention can occur and severely diminish quality of life. Regenerative strategies aimed at restoring LUT innervation are promising (Kim et al, 2013), and such efforts require a deeper understanding of the molecular processes governing the development of LUT innervation (Keast et al, 2015)

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