Trophic Effects of Brain-Derived Neurotrophic Factor Blockade in an Androgen-Sensitive Neuromuscular System

Abstract

In adult male rats, androgens are necessary for the maintenance of the motoneurons and their target muscles of the sexually dimorphic, steroid-sensitive spinal nucleus of the bulbocavernosus (SNB) neuromuscular system, regulating motoneuron and muscle morphology, function, and expression of trophic factors. Castration of males results in somal, dendritic, and muscle atrophy as well as increases in brain-derived neurotrophic factor (BDNF) in the target musculature. Because BDNF can have either facilitative or inhibitory effects in other systems, we examined SNB neuromuscular morphology after BDNF blockade using a fusion protein (tyrosine kinase receptor type B IgG). Blockade of BDNF in gonadally intact males resulted in hypertrophy of SNB motoneuron dendrites and target musculature, suggesting that normal levels of BDNF are inhibitory in SNB neuromuscular system. BDNF blockade in castrated males prevented SNB motoneuron atrophy and attenuated target muscle weight loss. This is the first demonstration that the highly androgen-sensitive SNB motoneuron dendrites and target muscles can be maintained in the absence of gonadal hormones and, furthermore, that blocking BDNF can have trophic effects on skeletal muscle. These results suggest that whereas BDNF is involved in the signaling cascade mediating the androgenic support of SNB neuromuscular morphology, its action can be inhibitory. Furthermore, the elevations in BDNF after castration may be responsible for the castration-induced atrophy in SNB motoneurons and target muscles, and the trophic effects of androgens may be mediated in part through a suppression of BDNF. These results may have relevance to therapeutic approaches to the treatment of neurodegenerative disease or myopathies.

Brain-derived neurotrophic factor and androgen interactions in spinal neuromuscular systems

“…Interestingly, castration markedly elevated BDNF protein in the SNB target musculature and treatment with trkB IgG prevented the typical castration-induced dendritic atrophy; dendrite lengths in these animals were similar to those of gonadally intact males treated with trkB IgG. This was the first demonstration that the dendritic arbors of the highly androgen-sensitive SNB motoneurons could be maintained in the absence of androgens, and further suggested that the elevated BDNF levels in muscle were responsible for regressive changes in SNB morphology (Verhovshek and Sengelaub, 2010b). Together, these results suggest that BDNF exerts regulatory effects on SNB dendrites, because when the actions of BDNF are blocked, dendritic hypertrophy occurs, and castration-induced somal atrophy is prevented.…”

“…Blockade of BDNF signaling using trkB IgG resulted in hypertrophy of the SNB target musculature in gonadally intact male rats, and muscle weights were significantly greater for trkB IgG-treated animals compared to controls (Verhovshek and Sengelaub, 2010b). Similarly, trkB IgG treatment in castrated males attenuated the castration-induced decrease in SNB target muscle weight (Verhovshek and Sengelaub, 2010b).…”

“…Castration decreases BDNF mRNA and protein in SNB motoneurons, and if BDNF signaling promotes the maintenance of SNB motoneuron morphology, these reductions could underlie the somal and dendritic regression seen after castration. Paradoxically, treating gonadally intact males with trkB IgG, a fusion protein that interrupts BDNF action, resulted in a hypertrophy of SNB dendritic arbors (Verhovshek and Sengelaub, 2010b; Fig. 2), suggesting that BDNF may be part of a signaling cascade exerting a tonic restraint on SNB motoneuron morphology.…”

Differential regulation of BDNF, synaptic plasticity and sprouting in the hippocampal mossy fiber pathway of male and female rats

“…It was suggested that testosterone exerts its protective effects by maintaining BDNF levels in dendrites, because testosterone treatment after gonadectomy restored BDNF levels in the motorneuron dendrites and prevented dendritic atrophy (Ottem et al 2007). On the other hand, trkB-IgG, a scavenger of BDNF, led to protection from the deleterious effects of castration on motorneurons; the authors suggested that testosterone normally suppresses BDNF levels (Verhovshek et al, 2010). …”

Hormones and the neuromuscular control of courtship in the golden-collared manakin (Manacus vitellinus)

“…This work shows that activation of AR within the LA muscles itself changes the morphology of the innervating motoneuron cell bodies within the SBN (Rand and Breedlove, 1995). This is thought to occur in part as a result of AR-dependent expression of brain-derived neurotrophic factor (BDNF) in the muscle cells, which is retrogradely transported from the muscle to the motoneuron soma (Verhovshek et al, 2010; Verhovshek et al, 2013) where it then acts via its receptor, tyrosine-related kinase B (trkB), to enhance motoneuron size and dendritic arbor (Verhovshek and Sengelaub, 2010). IGF-I produced locally in muscle tissue is also retrogradely transported to the spinal cord to induce neurotrophic effects (Kaspar et al, 2003; Dobrowolny et al, 2005).…”