title: Activity-dependent degeneration of axotomized neuromuscular synapses in Wld S mice.
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 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: 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 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.
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research, Hugh Robson Building, University of Edinburgh, George Square, Edinburgh EH8 9XD, UK.
authors.forename: R
authors.initials: R
authors.lastname: Brown
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research, Hugh Robson Building, University of Edinburgh, George Square, Edinburgh EH8 9XD, UK.
authors.forename: A
authors.initials: A
authors.lastname: Hynes-Allen
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research, Hugh Robson Building, University of Edinburgh, George Square, Edinburgh EH8 9XD, UK.
authors.forename: A J
authors.initials: AJ
authors.lastname: Swan
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research, Hugh Robson Building, University of Edinburgh, George Square, Edinburgh EH8 9XD, UK.
authors.forename: K N
authors.initials: KN
authors.lastname: Dissanayake
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research, Hugh Robson Building, University of Edinburgh, George Square, Edinburgh EH8 9XD, UK.
authors.forename: T H
authors.initials: TH
authors.lastname: Gillingwater
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research, Hugh Robson Building, University of Edinburgh, George Square, Edinburgh EH8 9XD, UK. Electronic address: Richard.Ribchester@ed.ac.uk.
authors.forename: R R
authors.initials: RR
authors.lastname: Ribchester
mesh_terms: D000818:Animals; D019771:Axotomy; D002118:Calcium / Q000378:metabolism; D004599:Electric Stimulation Therapy; D005260:Female; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009469:Neuromuscular Junction / Q000473:pathology / Q000503:physiopathology*; D012420:Running / Q000502:physiology; D012584:Sciatic Nerve / Q000187:drug effects / Q000503:physiopathology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D013979:Tibial Nerve / Q000293:injuries / Q000503:physiopathology; D046509:Tissue Culture Techniques; D014855:Wallerian Degeneration / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control
chemical_list: D009419:Nerve Tissue Proteins; D026941:Sodium Channel Blockers; C442580:Wld protein, mouse; D013779:Tetrodotoxin; D002118:Calcium
keywords: activity; axotomy; neuromuscular junction; synaptic plasticity