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.
Reviewing Editor
- Inna Slutsky, Tel Aviv University, Israel
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.
Version history
- Received: June 13, 2022
- Preprint posted: August 15, 2022 (view preprint)
- Accepted: July 6, 2023
- Accepted Manuscript published: July 11, 2023 (version 1)
- Version of Record published: July 24, 2023 (version 2)
- Version of Record updated: July 25, 2023 (version 3)
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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Huntingtin recruits KIF1A to transport synaptic vesicle precursors along the mouse axon to support synaptic transmission and motor skill learning
eLife 12:e81011.
https://doi.org/10.7554/eLife.81011
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The cytosolic proteins synucleins and synapsins are thought to play cooperative roles in regulating synaptic vesicle (SV) recycling, but mechanistic insight is lacking. Here, we identify the synapsin E-domain as an essential functional binding-partner of α-synuclein (α-syn). Synapsin E-domain allows α-syn functionality, binds to α-syn, and is necessary and sufficient for enabling effects of α-syn at synapses of cultured mouse hippocampal neurons. Together with previous studies implicating the E-domain in clustering SVs, our experiments advocate a cooperative role for these two proteins in maintaining physiologic SV clusters.
