1. Neuroscience

Dynamic neuromuscular remodeling precedes motor-unit loss in a mouse model of ALS

  1. Éric Martineau
  2. Adriana Di Polo
  3. Christine Vande Velde
  4. Richard Robitaille  Is a corresponding author
  1. Université de Montréal, Canada
https://doi.org/10.7554/eLife.41973
Share this article
Cite this article
  1. Éric Martineau
  2. Adriana Di Polo
  3. Christine Vande Velde
  4. Richard Robitaille
(2018)
Dynamic neuromuscular remodeling precedes motor-unit loss in a mouse model of ALS
eLife 7:e41973.
https://doi.org/10.7554/eLife.41973
  2. Download BibTeX
  3. Download .RIS

Abstract

Despite being an early event in ALS, it remains unclear whether the denervation of neuromuscular junctions (NMJ) is simply the first manifestation of a globally degenerating motor neuron. Using in vivo imaging of single axons and their NMJs over a three-month period, we identify that single motor-units are dismantled asynchronously in SOD1G37R mice. We reveal that weeks prior to complete axonal degeneration, the dismantling of axonal branches is accompanied by contemporaneous new axonal sprouting resulting in synapse formation onto nearby NMJs. Denervation events tend to propagate from the first lost NMJ, consistent with a contribution of neuromuscular factors extrinsic to motor neurons, with distal branches being more susceptible. These results show that NMJ denervation in ALS is a complex and dynamic process of continuous denervation and new innervation rather than a manifestation of sudden global motor neuron degeneration.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data has been provided for Figure 1, Figure 2 - Supplement 1, Figure 4, Figure 4 - Supplement 1, and Figure 5.

Article and author information

Author details

  1. Éric Martineau

    Département de neurosciences, Université de Montréal, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5503-0798

  2. Adriana Di Polo

    Département de neurosciences, Université de Montréal, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1430-0760

  3. Christine Vande Velde

    Département de neurosciences, Université de Montréal, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.

  4. Richard Robitaille

    Département de neurosciences, Université de Montréal, Montreal, Canada
    For correspondence
    richard.robitaille@umontreal.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6628-0146

Funding

Canadian Institutes of Health Research (MOP-111070)

  • Richard Robitaille

Canadian Foundation for Innovation

  • Christine Vande Velde
  • Richard Robitaille

ALS Society of Canada (Doctoral Research Award)

  • Éric Martineau

Muscular Dystrophy Association

  • Christine Vande Velde

Fonds de Recherche du Québec - Santé

  • Christine Vande Velde

Robert Packard Center for ALS research

  • Richard Robitaille

Canadian Institutes of Health Research (PJT-152934)

  • Adriana Di Polo

ALS Society of Canada

  • Christine Vande Velde

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Don W Cleveland, University of California, San Diego, United States

Ethics

Animal experimentation: All experiments were performed in accordance with the guidelines of the Canadian Council on Animal Care, the Comité de Déontologie sur l'Expérimentation Animale of Université de Montréal (protocol #18-040) and the CRCHUM Institutional Committee for the Protection of Animals (protocol #N16008CVV and #N15047ADPs).

Version history

  1. Received: September 13, 2018
  2. Accepted: October 14, 2018
  3. Accepted Manuscript published: October 15, 2018 (version 1)
  4. Version of Record published: November 13, 2018 (version 2)

Copyright

© 2018, Martineau et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,568
    views
  • 655
    downloads
  • 81
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Éric Martineau
  2. Adriana Di Polo
  3. Christine Vande Velde
  4. Richard Robitaille
(2018)
Dynamic neuromuscular remodeling precedes motor-unit loss in a mouse model of ALS
eLife 7:e41973.
https://doi.org/10.7554/eLife.41973

Share this article

https://doi.org/10.7554/eLife.41973

Categories and tags

Research organism

Further reading

    1. Neuroscience

    Clustered synapses develop in distinct dendritic domains in visual cortex before eye opening

    Alexandra H Leighton, Juliette E Cheyne, Christian Lohmann
    Research Article

    Synaptic inputs to cortical neurons are highly structured in adult sensory systems, such that neighboring synapses along dendrites are activated by similar stimuli. This organization of synaptic inputs, called synaptic clustering, is required for high-fidelity signal processing, and clustered synapses can already be observed before eye opening. However, how clustered inputs emerge during development is unknown. Here, we employed concurrent in vivo whole-cell patch-clamp and dendritic calcium imaging to map spontaneous synaptic inputs to dendrites of layer 2/3 neurons in the mouse primary visual cortex during the second postnatal week until eye opening. We found that the number of functional synapses and the frequency of transmission events increase several fold during this developmental period. At the beginning of the second postnatal week, synapses assemble specifically in confined dendritic segments, whereas other segments are devoid of synapses. By the end of the second postnatal week, just before eye opening, dendrites are almost entirely covered by domains of co-active synapses. Finally, co-activity with their neighbor synapses correlates with synaptic stabilization and potentiation. Thus, clustered synapses form in distinct functional domains presumably to equip dendrites with computational modules for high-capacity sensory processing when the eyes open.

    1. Neuroscience

    Multi-day neuron tracking in high-density electrophysiology recordings using earth mover’s distance

    Augustine Xiaoran Yuan, Jennifer Colonell ... Timothy D Harris
    Tools and Resources

    Accurate tracking of the same neurons across multiple days is crucial for studying changes in neuronal activity during learning and adaptation. Advances in high-density extracellular electrophysiology recording probes, such as Neuropixels, provide a promising avenue to accomplish this goal. Identifying the same neurons in multiple recordings is, however, complicated by non-rigid movement of the tissue relative to the recording sites (drift) and loss of signal from some neurons. Here, we propose a neuron tracking method that can identify the same cells independent of firing statistics, that are used by most existing methods. Our method is based on between-day non-rigid alignment of spike-sorted clusters. We verified the same cell identity in mice using measured visual receptive fields. This method succeeds on datasets separated from 1 to 47 days, with an 84% average recovery rate.

    1. Neuroscience

    Decision Making: Unraveling the enigmatic role of the subthalamic nucleus

    Qianli Yang
    Insight

    Subpopulations of neurons in the subthalamic nucleus have distinct activity patterns that relate to the three hypotheses of the Drift Diffusion Model.