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Activity-dependent degeneration of axotomized neuromuscular synapses in Wld(S) mice

Activity and disuse of synapses are thought to influence progression of several neurodegenerative diseases in which synaptic degeneration is an early sign. Here we tested whether stimulation or disuse renders neuromuscular synapses more or less vulnerable to degeneration, using axotomy as a robust t...

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Autores principales: Brown, R., Hynes-Allen, A., Swan, A.J., Dissanayake, K.N., Gillingwater, T.H., Ribchester, R.R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362769/
https://www.ncbi.nlm.nih.gov/pubmed/25617654
http://dx.doi.org/10.1016/j.neuroscience.2015.01.018
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author Brown, R.
Hynes-Allen, A.
Swan, A.J.
Dissanayake, K.N.
Gillingwater, T.H.
Ribchester, R.R.
author_facet Brown, R.
Hynes-Allen, A.
Swan, A.J.
Dissanayake, K.N.
Gillingwater, T.H.
Ribchester, R.R.
author_sort Brown, R.
collection PubMed
description Activity and disuse of synapses are thought to influence progression of several neurodegenerative diseases in which synaptic degeneration is an early sign. Here we tested whether stimulation or disuse renders neuromuscular synapses more or less vulnerable to degeneration, using axotomy as a robust trigger. We took advantage of the slow synaptic degeneration phenotype of axotomized neuromuscular junctions in flexor digitorum brevis (FDB) and deep lumbrical (DL) muscles of Wallerian degeneration-Slow (Wld(S)) mutant mice. First, we maintained ex vivo FDB and DL nerve-muscle explants at 32 °C for up to 48 h. About 90% of fibers from Wld(S) mice remained innervated, compared with about 36% in wild-type muscles at the 24-h checkpoint. Periodic high-frequency nerve stimulation (100 Hz: 1 s/100 s) reduced synaptic protection in Wld(S) preparations by about 50%. This effect was abolished in reduced Ca(2+) solutions. Next, we assayed FDB and DL innervation after 7 days of complete tetrodotoxin (TTX)-block of sciatic nerve conduction in vivo, followed by tibial nerve axotomy. Five days later, only about 9% of motor endplates remained innervated in the paralyzed muscles, compared with about 50% in 5 day-axotomized muscles from saline-control-treated Wld(S) mice with no conditioning nerve block. Finally, we gave mice access to running wheels for up to 4 weeks prior to axotomy. Surprisingly, exercising Wld(S) mice ad libitum for 4 weeks increased about twofold the amount of subsequent axotomy-induced synaptic degeneration. Together, the data suggest that vulnerability of mature neuromuscular synapses to axotomy, a potent neurodegenerative trigger, may be enhanced bimodally, either by disuse or by hyperactivity.
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spelling pubmed-43627692015-04-02 Activity-dependent degeneration of axotomized neuromuscular synapses in Wld(S) mice Brown, R. Hynes-Allen, A. Swan, A.J. Dissanayake, K.N. Gillingwater, T.H. Ribchester, R.R. Neuroscience Article Activity and disuse of synapses are thought to influence progression of several neurodegenerative diseases in which synaptic degeneration is an early sign. Here we tested whether stimulation or disuse renders neuromuscular synapses more or less vulnerable to degeneration, using axotomy as a robust trigger. We took advantage of the slow synaptic degeneration phenotype of axotomized neuromuscular junctions in flexor digitorum brevis (FDB) and deep lumbrical (DL) muscles of Wallerian degeneration-Slow (Wld(S)) mutant mice. First, we maintained ex vivo FDB and DL nerve-muscle explants at 32 °C for up to 48 h. About 90% of fibers from Wld(S) mice remained innervated, compared with about 36% in wild-type muscles at the 24-h checkpoint. Periodic high-frequency nerve stimulation (100 Hz: 1 s/100 s) reduced synaptic protection in Wld(S) preparations by about 50%. This effect was abolished in reduced Ca(2+) solutions. Next, we assayed FDB and DL innervation after 7 days of complete tetrodotoxin (TTX)-block of sciatic nerve conduction in vivo, followed by tibial nerve axotomy. Five days later, only about 9% of motor endplates remained innervated in the paralyzed muscles, compared with about 50% in 5 day-axotomized muscles from saline-control-treated Wld(S) mice with no conditioning nerve block. Finally, we gave mice access to running wheels for up to 4 weeks prior to axotomy. Surprisingly, exercising Wld(S) mice ad libitum for 4 weeks increased about twofold the amount of subsequent axotomy-induced synaptic degeneration. Together, the data suggest that vulnerability of mature neuromuscular synapses to axotomy, a potent neurodegenerative trigger, may be enhanced bimodally, either by disuse or by hyperactivity. Elsevier Science 2015-04-02 /pmc/articles/PMC4362769/ /pubmed/25617654 http://dx.doi.org/10.1016/j.neuroscience.2015.01.018 Text en © 2015 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Brown, R.
Hynes-Allen, A.
Swan, A.J.
Dissanayake, K.N.
Gillingwater, T.H.
Ribchester, R.R.
Activity-dependent degeneration of axotomized neuromuscular synapses in Wld(S) mice
title Activity-dependent degeneration of axotomized neuromuscular synapses in Wld(S) mice
title_full Activity-dependent degeneration of axotomized neuromuscular synapses in Wld(S) mice
title_fullStr Activity-dependent degeneration of axotomized neuromuscular synapses in Wld(S) mice
title_full_unstemmed Activity-dependent degeneration of axotomized neuromuscular synapses in Wld(S) mice
title_short Activity-dependent degeneration of axotomized neuromuscular synapses in Wld(S) mice
title_sort activity-dependent degeneration of axotomized neuromuscular synapses in wld(s) mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362769/
https://www.ncbi.nlm.nih.gov/pubmed/25617654
http://dx.doi.org/10.1016/j.neuroscience.2015.01.018
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