TrkB kinase activity maintains synaptic function and structural integrity at adult neuromuscular junctions

Carlos Bernardo Mantilla, Jessica M. Stowe, Dylan C. Sieck, Leonid G. Ermilov, Sarah M. Greising, Chao Zhang, Kevan M. Shokat, Gary C Sieck

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Activation of the tropomyosin-related kinase receptor B (TrkB) by brain-derived neurotrophic factor acutely regulates synaptic transmission at adult neuromuscular junctions (NMJs). The role of TrkB kinase activity in the maintenance of NMJ function and structure at diaphragm muscle NMJs was explored using a chemical-genetic approach that permits reversible inactivation of TrkB kinase activity in TrkBF616A mice by 1NMPP1. Inhibiting TrkB kinase activity for 7 days resulted in significant, yet reversible, impairments in neuromuscular transmission at diaphragm NMJs. Neuromuscular transmission failure following 2 min of repetitive phrenic nerve stimulation increased from 42% in control to 59% in 1NMPP1-treated TrkBF616A mice (P = 0.010). Recovery of TrkB kinase activity following withdrawal of 1NMPP1 treatment improved neuromuscular transmission (P = 0.006). Electrophysiological measurements at individual diaphragm NMJs documented lack of differences in quantal content in control and 1NMPP1-treated mice (P = 0.845). Morphological changes at diaphragm NMJs were modest following inhibition and recovery of TrkB kinase activity. Three-dimensional reconstructions of diaphragm NMJs revealed no differences in volume at motor end plates (labeled by α-bungarotoxin; P = 0.982) or presynaptic terminals (labeled by synaptophysin; P = 0.515). Inhibition of TrkB kinase activity by 1NMPP1 resulted in more compact NMJs, with increased apposition of presynaptic terminals and motor end plates (P = 0.017) and reduced fragmentation of motor end plates (P = 0.005). Recovery of TrkB kinase activity following withdrawal of 1NMPP1 treatment resulted in postsynaptic remodeling likely reflecting increased gutter depth (P = 0.007), without significant presynaptic changes. These results support an essential role for TrkB kinase activity in maintaining synaptic function and structural integrity at NMJs in the adult mouse diaphragm muscle.

Original languageEnglish (US)
Pages (from-to)910-920
Number of pages11
JournalJournal of Applied Physiology
Volume117
Issue number8
DOIs
StatePublished - Oct 15 2014

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Neuromuscular Junction
Phosphotransferases
Diaphragm
Motor Endplate
Presynaptic Terminals
trkB Receptor
tropomyosin kinase
Bungarotoxins
Muscles
Synaptophysin
Phrenic Nerve
Synaptic Transmission
Maintenance

Keywords

  • Diaphragm muscle
  • Innervation
  • Motor unit
  • Neuromuscular transmission
  • Synaptic plasticity

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

TrkB kinase activity maintains synaptic function and structural integrity at adult neuromuscular junctions. / Mantilla, Carlos Bernardo; Stowe, Jessica M.; Sieck, Dylan C.; Ermilov, Leonid G.; Greising, Sarah M.; Zhang, Chao; Shokat, Kevan M.; Sieck, Gary C.

In: Journal of Applied Physiology, Vol. 117, No. 8, 15.10.2014, p. 910-920.

Research output: Contribution to journalArticle

Mantilla, Carlos Bernardo ; Stowe, Jessica M. ; Sieck, Dylan C. ; Ermilov, Leonid G. ; Greising, Sarah M. ; Zhang, Chao ; Shokat, Kevan M. ; Sieck, Gary C. / TrkB kinase activity maintains synaptic function and structural integrity at adult neuromuscular junctions. In: Journal of Applied Physiology. 2014 ; Vol. 117, No. 8. pp. 910-920.
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