Huntingtin recruits KIF1A to transport synaptic vesicle precursors along the mouse axon to support synaptic transmission and motor skill learning

  1. Hélène Vitet
  2. Julie Bruyère
  3. Hao Xu
  4. Claire Séris
  5. Jacques Brocard
  6. Yah-Se Abada
  7. Benoît Delatour
  8. Chiara Scaramuzzino  Is a corresponding author
  9. Laurent Venance
  10. Frédéric Saudou  Is a corresponding author
  1. Université Grenoble Alpes, France
  2. University Grenoble Alpes, France
  3. College de France, CNRS, INSERM, Université PSL, France
  4. Sorbonne Université, Inserm U1127, CNRS UMR7225, France

Abstract

Neurotransmitters are released at synapses by synaptic vesicles (SVs), which originate from SV precursors (SVPs) that have traveled along the axon. Because each synapse maintains a pool of SVs, only a small fraction of which are released, it has been thought that axonal transport of SVPs does not affect synaptic function. Here, studying the corticostriatal network both in microfluidic devices and in mice, we find that phosphorylation of the Huntingtin protein (HTT) increases axonal transport of SVPs and synaptic glutamate release by recruiting the kinesin motor KIF1A. In mice, constitutive HTT phosphorylation causes SV over-accumulation at synapses, increases the probability of SV release, and impairs motor skill learning on the rotating rod. Silencing KIF1A in these mice restored SV transport and motor skill learning to wild-type levels. Axonal SVP transport within the corticostriatal network thus influences synaptic plasticity and motor skill learning.

Data availability

All datasets generated and analyzed during the study are included in the manuscript and in the supporting files. Source Data files have been provided for Figure 1, Figure 1- Figure Supplement 1, Figure 2, Figure 2- Figure Supplement 2, Figure 3, Figure 3- Figure Supplement 3, Figure 4, Figure 4- Figure Supplement 4, Figure 5, Figure 5- Figure Supplement 5, Figure 6, Figure 6- Figure Supplement 6, Figure 6- Figure Supplement 7, Figure 7, and Figure 8.

Article and author information

Author details

  1. Hélène Vitet

    INSERM U1216, Grenoble Institut Neurosciences, Université Grenoble Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Julie Bruyère

    INSERM U1216, Grenoble Institut Neurosciences, University Grenoble Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Hao Xu

    Center for Interdisciplinary Research in Biology, College de France, CNRS, INSERM, Université PSL, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Claire Séris

    INSERM U1216, Grenoble Institut Neurosciences, Université Grenoble Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Jacques Brocard

    INSERM U1216, Grenoble Institut Neurosciences, Université Grenoble Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0752-5737
  6. Yah-Se Abada

    Institut du Cerveau, Sorbonne Université, Inserm U1127, CNRS UMR7225, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Benoît Delatour

    Institut du Cerveau, Sorbonne Université, Inserm U1127, CNRS UMR7225, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Chiara Scaramuzzino

    INSERM U1216, Grenoble Institut Neurosciences, Université Grenoble Alpes, Grenoble, France
    For correspondence
    chiara.scaramuzzino@univ-grenoble-alpes.fr
    Competing interests
    The authors declare that no competing interests exist.
  9. Laurent Venance

    Center for Interdisciplinary Research in Biology, College de France, CNRS, INSERM, Université PSL, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0738-1662
  10. Frédéric Saudou

    INSERM U1216, Grenoble Institut Neurosciences, Université Grenoble Alpes, Grenoble, France
    For correspondence
    frederic.saudou@inserm.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6107-1046

Funding

European Research Council (834317)

  • Frédéric Saudou

Agence Nationale de la Recherche (ANR-15-IDEX-02 NeuroCoG)

  • Frédéric Saudou

Agence Nationale de la Recherche (ANR-18-CE16-0009-01 AXYON)

  • Frédéric Saudou

Fondation pour la Recherche Médicale (FRM,DEI20151234418)

  • Frédéric Saudou

Fondation pour la Recherche Médicale (SPF20140129405)

  • Chiara Scaramuzzino

European Molecular Biology Organization (ALTF 693-2015)

  • Chiara Scaramuzzino

Association Huntington France

  • Hélène Vitet

Fondation pour la Recherche Médicale (FDT201904008035)

  • Hélène Vitet

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 experimental procedures were performed in an authorized establishment (Grenoble Institut Neurosciences, INSERM U1216, license #B3851610008) in strict accordance with the directive of the European Community (63/2010/EU). The project was approved by the French Ethical Committee (Authorization number: APAFIS#18126-2018103018299125 v2) for care and use of laboratory animals and performed under the supervision of authorized investigators.

Copyright

© 2023, Vitet 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.

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