Huntingtin recruits KIF1A to transport synaptic vesicle precursors along the mouse axon to support synaptic transmission and motor skill learning
- Université Grenoble Alpes, France
- University Grenoble Alpes, France
- College de France, CNRS, INSERM, Université PSL, France
- 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
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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