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Author Notes:

Correspondence should be addressed to Dr. Kevin L. Seburn, Research Scientist, The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609. E-mail: kevin.seburn@jax.org.

R.W.B. and K.L.S. designed research.

E.L.S., J.N.S., K.H.M., and K.L.S. performed research.

M.J.P. contributed unpublished reagents/analytic tools.

E.L.S., J.N.S., and K.L.S. analyzed data.

K.L.S. wrote the paper.

For acknowledgments, please see the full article.

The authors declare no competing financial interests.

Subjects:

Research Funding:

This work was supported by R03-NS081334 (K.L.S.), RO1-NS054154 (R.W.B.).

The Scientific Services at Jackson are supported in part by NCI Cancer Center Support (CA034196).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • 3,4 diaminopyridine
  • axonal neuropathy
  • neuromuscular transmission
  • physostigmine
  • quantal content
  • voltage clamp
  • TRANSFER-RNA SYNTHETASE
  • TRANSMITTER RELEASE
  • IN-VIVO
  • PERIPHERAL NEUROPATHY
  • NERVE-TERMINALS
  • TRANSGENIC MICE
  • GENE MUTATION
  • ACTIVE ZONES
  • SHORT-TERM
  • GARS GENE

Synaptic Deficits at Neuromuscular Junctions in Two Mouse Models of Charcot-Marie-Tooth Type 2d

Tools:

Journal Title:

Journal of Neuroscience

Volume:

Volume 36, Number 11

Publisher:

, Pages 3254-3267

Type of Work:

Article | Final Publisher PDF

Abstract:

Patients with Charcot–Marie–Tooth Type 2D (CMT2D), caused by dominant mutations in Glycl tRNA synthetase (GARS), present with progressive weakness, consistently in the hands, but often in the feet also. Electromyography shows denervation, and patients often report that early symptoms include cramps brought on by cold or exertion. Based on reported clinical observations, and studies of mouse models of CMT2D, we sought to determine whether weakened synaptic transmission at the neuromuscular junction (NMJ) is an aspect of CMT2D. Quantal analysis of NMJs in two different mouse models of CMT2D (GarsP278KY, GarsC201R), found synaptic deficits that correlated with disease severity and progressed with age. Results of voltage-clamp studies revealed presynaptic defects characterized by: (1) decreased frequency of spontaneous release without any change in quantal amplitude (miniature endplate current), (2) reduced amplitude of evoked release (endplate current) and quantal content, (3) age-dependent changes in the extent of depression in response to repetitive stimulation, and (4) release failures at some NMJs with high-frequency, long-duration stimulation. Drugs that modify synaptic efficacy were tested to see whether neuromuscular performance improved. The presynaptic action of 3,4 diaminopyridine was not beneficial, whereas postsynaptic-acting physostigmine did improve performance. Smaller mutant NMJs with correspondingly fewer vesicles and partial denervation that eliminates some release sites also contribute to the reduction of release at a proportion of mutant NMJs. Together, these voltage-clamp data suggest that a number of release processes, while essentially intact, likely operate suboptimally at most NMJs of CMT2D mice.

Copyright information:

© 2016 the authors.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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