Axotomy-dependent and -independent synapse elimination in organ cultures of Wld(s) mutant mouse skeletal muscle

Simon H Parson, Richard R Ribchester, Neil Davie, Nirav P Gandhi, Rabia Q Malik, Thomas H Gillingwater, Derek Thomson

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Progressive "dying back" neurodegenerative diseases are debilitating due to loss of connectivity after nerve terminal and axonal withdrawal, which impairs peripheral nerve function and leads ultimately to neuronal cell death. The mutant mouse (Wallerian degeneration slow; Wld(s)) provides an accessible model system to understand orthograde and retrograde degeneration, because in these mice axotomy induces slow, progressive withdrawal of nerve terminals from motor endplates. Axon degeneration itself is about 10 times slower than in wild-type mice. We describe an organ culture paradigm that permits direct observation of the progressive changes in morphology of neuromuscular junctions in Wld(s) mutant mice. Normal nerve terminal and motor endplate morphology were maintained at most Wld(s) neuromuscular junctions for up to 72 hr in vitro. At others, synaptic boutons were removed from postsynaptic junctional folds in piecemeal fashion, as observed in adults in vivo. By contrast, nerve terminals degenerated rapidly and synchronously in wild-type muscle cultures, resembling Wallerian degeneration in vivo. These observations confirm that in Wld(s) mice, axotomy triggers a mechanism of nerve-terminal withdrawal that seems qualitatively different from that in wild-type animals. The piecemeal dismantling of presynaptic terminals resembles that occurring during neonatal synapse elimination. Organ cultures of neonatal Wld(s) muscle maintained for 1-2 days in vitro also showed no evidence of synaptic terminal degeneration, but elimination of polyneuronal innervation progressed in vitro at approximately the same rate as in vivo. Taken together, the data suggest that both natural and axotomy-induced forms of synapse withdrawal may be accessible to continuous observation and analysis, in organ-cultures of Wld(S) mouse muscles. This offers several advantages over repeated visualization of synaptic remodeling that has thus far been possible only in vivo.

Original languageEnglish
Pages (from-to)64-75
Number of pages12
JournalJournal of neuroscience research
Volume76
Issue number1
DOIs
Publication statusPublished - 1 Apr 2004

Fingerprint

Axotomy
Organ Culture Techniques
Synapses
Skeletal Muscle
Presynaptic Terminals
Motor Endplate
Wallerian Degeneration
Neuromuscular Junction
Muscles
Retrograde Degeneration
Observation
Wild Animals
Peripheral Nerves
Neurodegenerative Diseases
Axons
Cell Death
In Vitro Techniques

Keywords

  • Animals
  • Animals, Newborn
  • Axons
  • Axotomy
  • Image Processing, Computer-Assisted
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Fluorescence
  • Motor Endplate
  • Muscle, Skeletal
  • Neuromuscular Junction
  • Organ Culture Techniques
  • Presynaptic Terminals
  • Receptors, Cholinergic
  • Synapses
  • Wallerian Degeneration

Cite this

Axotomy-dependent and -independent synapse elimination in organ cultures of Wld(s) mutant mouse skeletal muscle. / Parson, Simon H; Ribchester, Richard R; Davie, Neil; Gandhi, Nirav P; Malik, Rabia Q; Gillingwater, Thomas H; Thomson, Derek.

In: Journal of neuroscience research, Vol. 76, No. 1, 01.04.2004, p. 64-75.

Research output: Contribution to journalArticle

Parson, Simon H ; Ribchester, Richard R ; Davie, Neil ; Gandhi, Nirav P ; Malik, Rabia Q ; Gillingwater, Thomas H ; Thomson, Derek. / Axotomy-dependent and -independent synapse elimination in organ cultures of Wld(s) mutant mouse skeletal muscle. In: Journal of neuroscience research. 2004 ; Vol. 76, No. 1. pp. 64-75.
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AU - Parson, Simon H

AU - Ribchester, Richard R

AU - Davie, Neil

AU - Gandhi, Nirav P

AU - Malik, Rabia Q

AU - Gillingwater, Thomas H

AU - Thomson, Derek

N1 - Copyright 2004 Wiley-Liss, Inc.

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N2 - Progressive "dying back" neurodegenerative diseases are debilitating due to loss of connectivity after nerve terminal and axonal withdrawal, which impairs peripheral nerve function and leads ultimately to neuronal cell death. The mutant mouse (Wallerian degeneration slow; Wld(s)) provides an accessible model system to understand orthograde and retrograde degeneration, because in these mice axotomy induces slow, progressive withdrawal of nerve terminals from motor endplates. Axon degeneration itself is about 10 times slower than in wild-type mice. We describe an organ culture paradigm that permits direct observation of the progressive changes in morphology of neuromuscular junctions in Wld(s) mutant mice. Normal nerve terminal and motor endplate morphology were maintained at most Wld(s) neuromuscular junctions for up to 72 hr in vitro. At others, synaptic boutons were removed from postsynaptic junctional folds in piecemeal fashion, as observed in adults in vivo. By contrast, nerve terminals degenerated rapidly and synchronously in wild-type muscle cultures, resembling Wallerian degeneration in vivo. These observations confirm that in Wld(s) mice, axotomy triggers a mechanism of nerve-terminal withdrawal that seems qualitatively different from that in wild-type animals. The piecemeal dismantling of presynaptic terminals resembles that occurring during neonatal synapse elimination. Organ cultures of neonatal Wld(s) muscle maintained for 1-2 days in vitro also showed no evidence of synaptic terminal degeneration, but elimination of polyneuronal innervation progressed in vitro at approximately the same rate as in vivo. Taken together, the data suggest that both natural and axotomy-induced forms of synapse withdrawal may be accessible to continuous observation and analysis, in organ-cultures of Wld(S) mouse muscles. This offers several advantages over repeated visualization of synaptic remodeling that has thus far been possible only in vivo.

AB - Progressive "dying back" neurodegenerative diseases are debilitating due to loss of connectivity after nerve terminal and axonal withdrawal, which impairs peripheral nerve function and leads ultimately to neuronal cell death. The mutant mouse (Wallerian degeneration slow; Wld(s)) provides an accessible model system to understand orthograde and retrograde degeneration, because in these mice axotomy induces slow, progressive withdrawal of nerve terminals from motor endplates. Axon degeneration itself is about 10 times slower than in wild-type mice. We describe an organ culture paradigm that permits direct observation of the progressive changes in morphology of neuromuscular junctions in Wld(s) mutant mice. Normal nerve terminal and motor endplate morphology were maintained at most Wld(s) neuromuscular junctions for up to 72 hr in vitro. At others, synaptic boutons were removed from postsynaptic junctional folds in piecemeal fashion, as observed in adults in vivo. By contrast, nerve terminals degenerated rapidly and synchronously in wild-type muscle cultures, resembling Wallerian degeneration in vivo. These observations confirm that in Wld(s) mice, axotomy triggers a mechanism of nerve-terminal withdrawal that seems qualitatively different from that in wild-type animals. The piecemeal dismantling of presynaptic terminals resembles that occurring during neonatal synapse elimination. Organ cultures of neonatal Wld(s) muscle maintained for 1-2 days in vitro also showed no evidence of synaptic terminal degeneration, but elimination of polyneuronal innervation progressed in vitro at approximately the same rate as in vivo. Taken together, the data suggest that both natural and axotomy-induced forms of synapse withdrawal may be accessible to continuous observation and analysis, in organ-cultures of Wld(S) mouse muscles. This offers several advantages over repeated visualization of synaptic remodeling that has thus far been possible only in vivo.

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KW - Muscle, Skeletal

KW - Neuromuscular Junction

KW - Organ Culture Techniques

KW - Presynaptic Terminals

KW - Receptors, Cholinergic

KW - Synapses

KW - Wallerian Degeneration

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JO - Journal of neuroscience research

JF - Journal of neuroscience research

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