Electrophysiological effects of BDNF and TrkB signaling at type-identified diaphragm neuromuscular junctions

Carlos B. Mantilla, Leonid G. Ermilov, Sarah M. Greising, Heather M. Gransee, Wen Zhi Zhan, Gary C. Sieck

Research output: Contribution to journalArticlepeer-review


Previous studies show that synaptic quantal release decreases during repetitive stimulation, i.e., synaptic depression. Neurotrophin brain-derived neurotrophic factor (BDNF) enhances neuromuscular transmission via activation of tropomyosinrelated 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 for 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). The 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.

Original languageEnglish (US)
Pages (from-to)781-792
Number of pages12
JournalJournal of neurophysiology
Issue number4
StatePublished - Apr 2023

Bibliographical note

Publisher Copyright:
© 2023 the American Physiological Society.


  • brain-derived neurotrophic factor
  • motor unit
  • synaptic efficacy
  • transmission failure
  • tropomyosin-related kinase receptor subtype B

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural


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