Morphological and functional changes in innervation of a fast forelimb muscle in SOD1-G85R mice

Khanh T. Nguyen, Zhongsheng Zhang, Ellen F. Barrett, Gavriel David

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Muscle endplates become denervated in mice that express mutations of human superoxide dismutase 1 (hSOD1), models of familial amyotrophic lateral sclerosis. This denervation is especially marked in fast limb muscles, and precedes death of motor neuron somata. This study used mice that expressed yellow fluorescent protein (YFP) in neurons to investigate changes in the morphology and function of axons and motor terminals innervating a fast forelimb muscle (epitrochleoanconeus, ETA) in presymptomatic and symptomatic hSOD1-G85R mice, compared to those in mice that express wild-type (wt) hSOD1. The percentage of endplates (identified using fluorescently-labeled α-bungarotoxin) innervated by motor terminals remained high in presymptomatic SOD1-G85R mice, but fell to ~50% in symptomatic mice. The number of large diameter (≥4μm) axons in the ETA nerve also decreased as mice became symptomatic, and endplate innervation correlated best with the number of large diameter axons. Motor terminal function was assessed using changes in terminal YFP fluorescence evoked by trains of action potentials; different components of the pH-dependent YFP signals reflect stimulation-induced Ca2+ entry and vesicular exo/endocytosis. Most visible motor terminals (>90%) remained capable of responding to nerve stimulation in both pre- and symptomatic hSOD1-G85R mice, but with functional alterations. Responses in presymptomatic terminals suggested reduced acidification and increased vesicular release, whereas symptomatic terminals exhibited increased acidification and reduced vesicular release. The fact that most remaining terminals were able to respond to nerve stimulation suggests that motor terminal-protective therapies might contribute to preserving neuromuscular function in fALS mice.

Original languageEnglish (US)
Pages (from-to)399-408
Number of pages10
JournalNeurobiology of Disease
Volume48
Issue number3
DOIs
StatePublished - Dec 2012

Keywords

  • Calcium
  • Cytosolic pH
  • Denervation
  • Exocytosis
  • Familial amyotrophic lateral sclerosis
  • Motor axon
  • Motor nerve terminal
  • Neuromuscular junction
  • Superoxide dismutase 1 G85R
  • Yellow fluorescent protein

ASJC Scopus subject areas

  • Neurology

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