LAUSR

Previous studies show that synaptic quantal release decreases during repetitive stimulation, i.e., synaptic depression. The neurotrophin brain-derived neurotrophic factor (BDNF) enhances neuromuscular transmission via activation of tropomyosin-related kinase receptor B (TrkB). We hypothesized that BDNF mitigates synaptic depression at the neuromuscular junction and that the effect is more pronounced at type IIx and/or IIb fibers compared to type I or IIa fibers given the more rapid reduction in docked synaptic vesicles with repetitive stimulation. Rat phrenic nerve-diaphragm muscle preparations were used to determine the effect of BDNF on synaptic quantal release during repetitive stimulation at 50 Hz. An ~40% decline in quantal release was observed during each 330 ms duration train of nerve stimulation (intratrain synaptic depression) and this intratrain decline was observed across repetitive trains (20 trains at 1/s repeated every 5 min for 30 min - 6 sets). BDNF treatment significantly enhanced quantal release at all fiber types (p<0.001). BDNF treatment did not change release probability within a stimulation set but enhanced synaptic vesicle replenishment between sets. In agreement, synaptic vesicle cycling (measured using FM4-64 fluorescence uptake) was increased following BDNF (or neurotrophin-4; NT-4) treatment (~40%; p<0.05). Conversely, inhibiting BDNF/TrkB signaling with the tyrosine kinase inhibitor K252a and TrkB-IgG (which quenches endogenous BDNF or NT-4) decreased FM4-64 uptake (~34% across fiber types; p<0.05). Effects of BDNF were generally similar across all fiber types. We conclude that BDNF/TrkB signaling acutely enhances presynaptic quantal release, and thereby may serve to mitigate synaptic depression and maintain neuromuscular transmission during repetitive activation.