Neurotrophic Factor Mechanisms Underlying the Development and Plasticity of Pelvic Ganglia

Pelvic ganglia provide the majority of the motor innervation to the urogenital organs.1 These ganglia form a particularly interesting and complex area of the peripheral nervous system because they are mixed and contain similar numbers of sympathetic and parasympathetic neurons, as well as spinal inputs from diverse levels. Many pelvic ganglion neurons and their connections to pelvic organs are highly susceptible to injury during pelvic surgery (such as prostatectomy, hysterectomy, and lower bowel resection for tumor removal). Moreover, damage to their central control pathways because of spinal cord injury or cauda equina syndrome leads to permanent structural and chemical changes. Metabolic disorders, such as diabetes, can also profoundly affect the structure and function of pelvic ganglion neurons. Therefore, there are numerous neurobiological and medical reasons to understand the properties and behavior of these ganglia. A common theme in modern regeneration research is that key aspects of axonal regrowth may recapitulate the events that occur during the initial growth of an axon in early development. While many aspects of immature and adult neurons differ, this analogy has proven to be a useful tool in identifying and exploring new potential therapeutic targets. Two major groups of substances that influence the development of pelvic ganglion neurons are gonadal steroids and neurotrophic factors. Most studies exploring these substances in pelvic ganglia have focused on male rodents, where testosterone plays a major role to determine sexually-dimorphic aspects of this innervation (e.g. in males, more numerous sympathetic neurons, heavier sympathetic innervation of reproductive organs).2 Gonadal steroids continue to cause physiological effects on adult pelvic ganglion neurons, where their growth-related actions have been studied in most detail, but the effects on transmitter synthesis and electrophysiological parameters have also been identified.1 Testosterone actions on axonal growth are especially interesting because they are partly mediated by estrogens, due to the expression of aromatase in the pelvic ganglion (aromatase converts testosterone to estradiol).3 Therefore, agents that affect estrogen synthesis or signaling could be effective stimulants of regenerative growth. Neurotrophic factors also have important effects during development and determine the final projections of neurons to their appropriate targets. My research group is particularly interested in the neurotrophic factors responsible for the development and targeting of parasympathetic pelvic neurons.4 While neurturin and its relative, glial cell line-derived neurotrophic factor (GNDF), are essential for the differentiation and projection of some groups of pelvic ganglion neurons, especially those innervating reproductive organs, we believe that additional target-derived substances are important. For example, neurturin or GDNF gene deletions do not impair bladder innervation; therefore, alternative mechanisms of regulating development of bladder parasympathetic neurons must exist. Gene knockout and neuronal culture studies have shown that neurturin is a powerful neurotrophic factor for adult nitrergic parasympathetic pelvic neurons, most of which innervate the reproductive organs. In cultured male rat pelvic ganglion neurons, neurturin causes neurite initiation and elongation via a PI3 kinase-dependent mechanism.5 The nitrergic innervation of reproductive organs is structurally deficient in neurturin knockout mice.6 Very few nitrergic axons are present in the corpus cavernosum of the penis of these mice, yet mating is still successful, implying that functional compensation must occur. We have found that there is increased responsiveness to acetylcholine, which we presume must overcome the reduced neuronal release sites.7 In contrast, when we denervated the cavernosal muscle, there was a decreased responsiveness to nitric oxide (e.g. response to the nitric oxide donor, sodium nitroprusside).8 This impeded the return of erectile function, even when nitrergic axons had regrown to their original targets. These studies show not only that neurturin is important for the development and maintenance of pelvic parasympathetic axons, but also that postganglionic innervation of pelvic viscera has a remarkable degree of plasticity. Understanding the basis of this plasticity allows us to target pro-regenerative therapies to the location and time period that provide