We will examine the influence of steroid hormones, specifically androgens, on a neuromuscular system that responds to these hormones throughout life. Previous work has shown that androgens maintain the bulbocavernosus (BC) and levator ani (LA) muscles of developing male rats. These striated perineal muscles are normally present in females at birth but, in the absence of androgen, the muscles die. A single injection of androgen to newborn female rats will preserve the muscles for life. The BC/LA muscles are innervated by motoneurons in the spinal nucleus of the bulbocavernosus (SNB). Androgenic sparing of the BC/LA target muscles also indirectly spares the SNB motoneurons from developmental apoptosis. The present project will study the effects that androgenic hormones continue to exert on the SNB system in adulthood. Castration of adult male rats triggers a host of changes in the structure and function of the SNB system. For example, the somata and dendrites of SNB motoneurons, as well as the neuromuscular junctions (NMJs) these motoneurons make upon the target muscles, shrink following castration. Testosterone (T) therapy can prevent and/or reverse this shrinkage. We have found that T cannot maintain SNB somata size when we pharmacologically block the N-methyl-d-aspartate (NMDA) type glutamate receptor. This effect of NMDA blockade seems to be specific to SNB motoneurons and to the effect of T. We propose to determine whether NMDA blockade also prevents the effects of T on SNB dendrites and NMJs. We have found that SNB motoneurons, but not other nearby motoneurons, increase their expression of the gene for the NMDA receptor subtype 1 (NMDAR1). So the androgen-induced increase in NMDA receptor stimulation of SNB motoneurons may contribute to maintaining soma size. We will use a mosaic analysis to ask whether androgen acts directly upon SNB motoneurons to increase their expression of the NMDAR1 message. We will also determine whether SNB motoneurons express a newly discovered NMDA receptor subtype (NMDAR3), whether androgen manipulations alter NMDAR3 expression, and if so whether this is a cell-autonomous response of the motoneurons. These studies should lead to a better understanding of neuromuscular systems, of the influence of steroid hormones on the spinal cord, and the etiology of several neuromuscular disorders including amyotrophic lateral sclerosis and Kennedy's syndrome.
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