Development of abnormalities at the neuromuscular junction in the SOD1-G93A mouse model of ALS : dysfunction then disruption of postsynaptic structure precede motor symptoms
Abstract
The ultimate deficit in ALS is neuromuscular junction (NMJ) loss, producing permanent paralysis, ultimately in respiratory muscles. However, understanding the functional and structural deficits at NMJs prior to this loss is crucial for therapeutic strategy design. Should early interventions focus on reversing denervation, or supporting largely intact NMJs that are functionally impaired? We therefore determined when functional and structural deficits appeared in diaphragmatic NMJs relative to the onset of hindlimb tremor (the first overt motor symptoms) in vivo in the SOD1-G93A mouse model of ALS. Significant reduction in the amplitudes of spontaneous miniature endplate potentials (mEPPs) and evoked EPPs emerged only at early symptomatic ages (in our colony, 18-22 weeks). Reductions in mEPP frequency, number of vesicles per EPP, and EPP rise time were seen earlier, at 16weeks, but this reversed by early symptomatic ages. However, the earliest and most striking impairment was an inability to maintain EPP amplitude during a 20 Hz stimulus train, which appeared 6 weeks before overt in vivo motor symptoms. Despite this, fluorescent α-bungarotoxin labelling revealed no systematic, progressive changes in 11 comprehensive NMJ morphological parameters (area, shape, compactness, number of acetylcholine receptor, AChR, regions, etc.) with disease progression. Rather, while NMJs were largely normally-shaped, from 16 weeks there was a progressive and substantial disruption in AChR concentration and distribution within the NMJ footprint. Thus, NMJ functional deficits appear at least 6 weeks before motor symptoms in vivo, while structural deficits occur 4 weeks later, and predominantly within NMJs. These data suggest initial therapies focused on rectifying suboptimal NMJ function could produce effective relief of symptoms of weakness.
Citation
McIntosh , J , Mekrouda , I , Dashti , M , Giuraniuc , C , Banks , R W , Miles , G B & Bewick , G S 2023 , ' Development of abnormalities at the neuromuscular junction in the SOD1-G93A mouse model of ALS : dysfunction then disruption of postsynaptic structure precede motor symptoms ' , Frontiers in Molecular Neuroscience , vol. 16 , 1169075 . https://doi.org/10.3389/fnmol.2023.1169075
Publication
Frontiers in Molecular Neuroscience
Status
Peer reviewed
ISSN
1662-5099Type
Journal article
Rights
Copyright © 2023 McIntosh, Mekrouda, Dashti, Giuraniuc, Banks, Miles and Bewick. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Description
Funding: This project was funded by a PhD studentship to JM from Motor Neurone Disease Scotland, on grant number RGB5753 to GSB and GBM.Collections
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