Identification of a stereotypic molecular arrangement of endogenous glycine receptors at spinal cord synapses

  1. Stephanie Maynard
  2. Philippe Rostaing
  3. Natascha Schaefer
  4. Olivier Gemin
  5. Adrien Candat
  6. Andréa Dumoulin
  7. Carmen Villmann
  8. Antoine Triller
  9. Christian G Specht  Is a corresponding author
  1. Institut de Biologie de l'ENS (IBENS), PSL University, France
  2. University of Wuerzburg, Germany
  3. Inserm U1195, Université Paris-Saclay, France

Abstract

Precise quantitative information about the molecular architecture of synapses is essential to understanding the functional specificity and downstream signaling processes at specific populations of synapses. Glycine receptors (GlyRs) are the primary fast inhibitory neurotransmitter receptors in the spinal cord and brainstem. These inhibitory glycinergic networks crucially regulate motor and sensory processes. Thus far the nanoscale organization of GlyRs underlying the different network specificities has not been defined. Here, we have quantitatively characterized the molecular arrangement and ultra-structure of glycinergic synapses in spinal cord tissue using quantitative super-resolution correlative light and electron microscopy (SR-CLEM). We show that endogenous GlyRs exhibit equal receptor-scaffold occupancy and constant packing densities of about 2000 GlyRs µm-2 at synapses across the spinal cord and throughout adulthood, even though ventral horn synapses have twice the total copy numbers, larger postsynaptic domains and more convoluted morphologies than dorsal horn synapses. We demonstrate that this stereotypic molecular arrangement is maintained at glycinergic synapses in the oscillator mouse model of the neuromotor disease hyperekplexia despite a decrease in synapse size, indicating that the molecular organization of GlyRs is preserved in this hypomorph. We thus conclude that the morphology and size of inhibitory postsynaptic specializations rather than differences in GlyR packing determine the postsynaptic strength of glycinergic neurotransmission in motor and sensory spinal cord networks.

Data availability

Upon acceptance, all source data of this publication will be made available through a data repository.

Article and author information

Author details

  1. Stephanie Maynard

    Institut de Biologie de l'ENS (IBENS), PSL University, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7838-3676
  2. Philippe Rostaing

    Institut de Biologie de l'ENS (IBENS), PSL University, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Natascha Schaefer

    Institute for Clinical Neurobiology, University of Wuerzburg, Wuerzburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9743-1963
  4. Olivier Gemin

    Institut de Biologie de l'ENS (IBENS), PSL University, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3210-7876
  5. Adrien Candat

    Institut de Biologie de l'ENS (IBENS), PSL University, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Andréa Dumoulin

    Institut de Biologie de l'ENS (IBENS), PSL University, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Carmen Villmann

    Institute for Clinical Neurobiology, University of Wuerzburg, Wuerzburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1498-6950
  8. Antoine Triller

    Institut de Biologie de l'ENS (IBENS), PSL University, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7530-1233
  9. Christian G Specht

    Diseases and Hormones of the Nervous System (DHNS), Inserm U1195, Université Paris-Saclay, Paris, France
    For correspondence
    christian.specht@inserm.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6038-7735

Funding

H2020 European Research Council (Plastinhib)

  • Antoine Triller

Agence Nationale de la Recherche (Synaptune)

  • Antoine Triller

Agence Nationale de la Recherche (Syntrack)

  • Antoine Triller

Labex (Memolife)

  • Antoine Triller

France Bio-Imaging

  • Antoine Triller

Deutsche Forschungsgemeinschaft (VI586)

  • Carmen Villmann

Fondation pour la Recherche Médicale (SPF201809007132)

  • Stephanie Maynard

Bavarian State Ministry of Science and the Arts and the University of Würzburg (Graduate School of Life Sciences (GSLS))

  • Natascha Schaefer

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

Ethics

Animal experimentation: All experiments were in accordance with European Union guidelines and approved by the local veterinary authorities. Animals at IBENS were treated in accordance with the guidelines of the French Ministry of Agriculture and Direction Départementale des Services Vétérinaires de Paris (École Normale Supérieure, Animalerie des Rongeurs, license B 75-05-20). Procedures carried out at the Institute for Clinical Neurobiology were approved by the Veterinäramt der Stadt Würzburg and the Committee on the Ethics of Animal Experiments (Regierung von Unterfranken, Würzburg) and authorized under reference numbers 55.2-2531.01-09/14; 55.2.2-2532.2-949-31.

Copyright

© 2021, Maynard 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

  • 1,353
    views
  • 196
    downloads
  • 17
    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. Stephanie Maynard
  2. Philippe Rostaing
  3. Natascha Schaefer
  4. Olivier Gemin
  5. Adrien Candat
  6. Andréa Dumoulin
  7. Carmen Villmann
  8. Antoine Triller
  9. Christian G Specht
(2021)
Identification of a stereotypic molecular arrangement of endogenous glycine receptors at spinal cord synapses
eLife 10:e74441.
https://doi.org/10.7554/eLife.74441

Share this article

https://doi.org/10.7554/eLife.74441

Further reading

    1. Neuroscience
    Friedrich Schuessler, Francesca Mastrogiuseppe ... Omri Barak
    Research Article

    The relation between neural activity and behaviorally relevant variables is at the heart of neuroscience research. When strong, this relation is termed a neural representation. There is increasing evidence, however, for partial dissociations between activity in an area and relevant external variables. While many explanations have been proposed, a theoretical framework for the relationship between external and internal variables is lacking. Here, we utilize recurrent neural networks (RNNs) to explore the question of when and how neural dynamics and the network’s output are related from a geometrical point of view. We find that training RNNs can lead to two dynamical regimes: dynamics can either be aligned with the directions that generate output variables, or oblique to them. We show that the choice of readout weight magnitude before training can serve as a control knob between the regimes, similar to recent findings in feedforward networks. These regimes are functionally distinct. Oblique networks are more heterogeneous and suppress noise in their output directions. They are furthermore more robust to perturbations along the output directions. Crucially, the oblique regime is specific to recurrent (but not feedforward) networks, arising from dynamical stability considerations. Finally, we show that tendencies toward the aligned or the oblique regime can be dissociated in neural recordings. Altogether, our results open a new perspective for interpreting neural activity by relating network dynamics and their output.

    1. Neuroscience
    Sudhanvan Iyer, Kathryn Maxson Jones ... Mary A Majumder
    Review Article

    In this paper, we provide an overview and analysis of the BRAIN Initiative data-sharing ecosystem. First, we compare and contrast the characteristics of the seven BRAIN Initiative data archives germane to data sharing and reuse, namely data submission and access procedures and aspects of interoperability. Second, we discuss challenges, benefits, and future opportunities, focusing on issues largely specific to sharing human data and drawing on N = 34 interviews with diverse stakeholders. The BRAIN Initiative-funded archive ecosystem faces interoperability and data stewardship challenges, such as achieving and maintaining interoperability of data and archives and harmonizing research participants’ informed consents for tiers of access for human data across multiple archives. Yet, a benefit of this distributed archive ecosystem is the ability of more specialized archives to adapt to the needs of particular research communities. Finally, the multiple archives offer ample raw material for network evolution in response to the needs of neuroscientists over time. Our first objective in this paper is to provide a guide to the BRAIN Initiative data-sharing ecosystem for readers interested in sharing and reusing neuroscience data. Second, our analysis supports the development of empirically informed policy and practice aimed at making neuroscience data more findable, accessible, interoperable, and reusable.