TrkB signaling modulates neuromuscular transmission in a frequency dependent manner in the mouse diaphragm muscle.

Signaling via tropomyosin-related kinase receptor B (TrkB) plays an important role in synaptic function and plasticity at the neuromuscular junction. Multiple conditions show selective effects on the most forceful and fatigable motor units that require high frequency activation and are necessary for maximal force generation. The goal of the present study is to investigate the effects of inhibiting TrkB kinase activity on neuromuscular transmission in mouse diaphragm muscle during repeated stimulation at frequencies that reflect the recruitment of different motor units (10 vs. 75 Hz). TrkBF616A mice, which possess a mutation that renders TrkB kinase activity susceptible to rapid inhibition by 1NMPP1, were used at 6-8 months old (n = 12; 6 females). Neuromuscular transmission failure (NMTF) was estimated in diaphragm-phrenic nerve preparations following 1 hour treatment with 1NMPP1 or vehicle by assessing the difference in forces evoked by 2 min of repetitive nerve and muscle stimulation at either 10 or 75 Hz. There was no effect of 1NMPP1 on muscle contractile properties, but there was a frequency-dependent effect of 1NMPP1 treatment on the extent of NMTF. At 10 Hz stimulation, 1NMPP1 decreased the extent of NMTF compared to vehicle by 35%. At 75 Hz, 1NMPP1 increased the extent of NMTF compared to vehicle by 28%. The greater negative effect of TrkB kinase inhibition during higher frequency stimulation suggests reliance on TrkB signaling for sustained activation predominantly at higher force, more fatigable motor units which are responsible for the high forces necessary for airway clearance (i.e., coughing and sneezing).