TrkB kinase activity maintains synaptic function and structural integrity at adult neuromuscular junctions
Carlos B Mantilla1, Jessica M Stowe2, Dylan C Sieck2
1Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota; Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota; and mantilla.carlos@mayo.edu.
Journal of Applied Physiology (Bethesda, Md. : 1985)
|August 30, 2014
Summary
TrkB kinase activity is essential for maintaining neuromuscular junction (NMJ) function and structure in adult diaphragm muscles. Inhibiting TrkB kinase reversibly impairs neuromuscular transmission and alters NMJ morphology.
Area of Science:
- Neuroscience
- Muscle Physiology
- Molecular Biology
Background:
- Brain-derived neurotrophic factor (BDNF) activates tropomyosin-related kinase receptor B (TrkB), acutely regulating synaptic transmission at adult neuromuscular junctions (NMJs).
- The specific role of TrkB kinase activity in the long-term maintenance of NMJ function and structure, particularly in the diaphragm muscle, remained less understood.
Purpose of the Study:
- To investigate the necessity of TrkB kinase activity for the maintenance of neuromuscular junction (NMJ) function and structural integrity in adult mouse diaphragm muscle.
- To explore the effects of reversible TrkB kinase inhibition on neuromuscular transmission and NMJ morphology.
Main Methods:
- A chemical-genetic approach using TrkB(F616A) mice treated with 1NMPP1 to achieve reversible TrkB kinase inactivation.
- Assessment of neuromuscular transmission via repetitive phrenic nerve stimulation and electrophysiological measurements at individual diaphragm NMJs.
- Morphological analysis of diaphragm NMJs using three-dimensional reconstructions and specific labeling of pre- and postsynaptic components.
Main Results:
- Seven-day inhibition of TrkB kinase activity significantly impaired neuromuscular transmission, increasing failure rates during repetitive stimulation, an effect that was reversible upon drug withdrawal.
- While quantal content remained unchanged, TrkB inhibition led to more compact NMJs with increased apposition and reduced fragmentation of motor end plates.
- Postsynaptic remodeling, including increased gutter depth, was observed upon recovery of TrkB kinase activity, without significant presynaptic alterations.
Conclusions:
- TrkB kinase activity is crucial for maintaining synaptic function and structural integrity at adult mouse diaphragm neuromuscular junctions.
- Reversible inhibition of TrkB kinase activity leads to functional impairments and specific morphological changes at the NMJ.
- These findings highlight the essential role of TrkB signaling in the ongoing maintenance of neuromuscular junctions in adult skeletal muscle.
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