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

Rosalind Brown, A Hynes-Allen, A J Swan, K N Dissanayake, T H Gillingwater, R R Ribchester

Research output: Contribution to journalArticlepeer-review

Abstract

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 48h. 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 (100Hz: 1s/100s) 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 7days 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 5day-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 4weeks prior to axotomy. Surprisingly, exercising Wld(S) mice ad libitum for 4weeks 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.

Original languageEnglish
Pages (from-to)300-320
Number of pages21
JournalNeuroscience
Volume290C
DOIs
Publication statusPublished - 21 Jan 2015

Keywords

  • neuromuscular junction
  • axotomy
  • synaptic plasticity
  • activity
  • AMYOTROPHIC-LATERAL-SCLEROSIS
  • AXONAL-TRANSPORT BLOCKADE
  • MOTOR-NERVE TERMINALS
  • ADULT-RAT MUSCLE
  • PROFESSIONAL FOOTBALL PLAYERS
  • BUNGAROTOXIN-TREATED RATS
  • MOUSE SKELETAL-MUSCLE
  • WLD(S) MUTANT MOUSE
  • WALLERIAN DEGENERATION
  • TRANSGENIC MICE

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