Early and Selective Loss of Neuromuscular Synapse Subtypes with Low Sprouting Competence in Motoneuron Diseases
By Dunja Frey, C. Schneider, Lan Xu, J. Borg, Will Spooren, P. Caroni. Journal of Neuroscience, 2000
694 citations recorded by the source corpus.
The addition or loss of synapses in response to changes in activity, disease, or aging is a major aspect of nervous system plasticity in the adult. The mechanisms that affect the turnover and maintenance of synapses in the adult are poorly understood and are difficult to investigate in the brain. Here, we exploited a unique anatomical arrangement in the neuromuscular system to determine whether subtypes of synapses can differ in anatomical plasticity and vulnerability. In three genetic mouse models of motoneuron disease of diverse origin and severity, we observed a gradual and selective loss of synaptic connections that begun long before the onset of clinical deficits and correlated with the timing of disease progression. A subgroup of fast-type (fast-fatiguable) neuromuscular synapses was highly vulnerable and was lost very early on. In contrast, slow-type synapses resisted up to the terminal phase of the disease. Muscle-specific differences were also evident. Similar selective losses were detected in aged mice. These selective vulnerability properties of synapses coincided with hitherto unrecognized major differences in stimulus-induced anatomical plasticity that could also be revealed in healthy mice. Using paralysis and/or growth-associated protein 43 overexpression to induce synaptic sprouting, we found that slow-type, disease-resistant synapses were particularly plastic. In contrast, fast-type synapses with the highest vulnerability failed to exhibit any stimulus-induced change. The results reveal pronounced subtype specificity in the anatomical plasticity and susceptibility to loss of neuromuscular synapses and suggest that degenerative motoneuron diseases involve a common early pathway of selective and progressive synaptic weakening also associated with aging.
Subfields: Molecular Biology, Neurology
View Paper: https://www.semanticscholar.org/paper/80b6d8dc75b5fa35ea32cf8cc6532ad6270a212c
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Citations in the corpus
- Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF (2006, background): “, more accessible synapses between motoneurons and muscles are also lost early on and in reproducible pattern”
- Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. (2004, methodology): “There is a general acceptance that weakness and death in the SOD1 G93A mutant mouse, and in humans with ALS, occur as a direct consequence of motor neuron death.”
- Synaptic energy use and supply. (2012, neutral): “When this pathway is deranged, as occurs with mutations in PINK1 or Parkin that give rise to hereditary forms of Parkinson’s disease (Kitada et al., 1998; Valente et al., 2004), malfunctioning mitochondria will not provide sufficient ATP at synapses.”
- Gap43, Marcks, and Cap23 Modulate Pi(4,5p)2 at Plasmalemmal Rafts, and Regulate Cell Cortex Actin Dynamics through a Common Mechanism (2000, methodology): “However, in addition, a large proportion of medial gastrocnemius synapses that do not sprout in wild-type mice, nor in Thy1GAP43 mice (Frey et al., 2000b), did so in the presence of GAP43(DED) (Fig.”