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.
Metrics
-
- 1,223
- views
-
- 253
- downloads
-
- 4
- 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)
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
Further reading
-
- Neuroscience
Chronic back pain (CBP) is a global health concern with significant societal and economic burden. While various predictors of back pain chronicity have been proposed, including demographic and psychosocial factors, neuroimaging studies have pointed to brain characteristics as predictors of CBP. However, large-scale, multisite validation of these predictors is currently lacking. In two independent longitudinal studies, we examined white matter diffusion imaging data and pain characteristics in patients with subacute back pain (SBP) over 6- and 12-month periods. Diffusion data from individuals with CBP and healthy controls (HC) were analyzed for comparison. Whole-brain tract-based spatial statistics analyses revealed that a cluster in the right superior longitudinal fasciculus (SLF) tract had larger fractional anisotropy (FA) values in patients who recovered (SBPr) compared to those with persistent pain (SBPp), and predicted changes in pain severity. The SLF FA values accurately classified patients at baseline and follow-up in a third publicly available dataset (Area under the Receiver Operating Curve ~0.70). Notably, patients who recovered had FA values larger than those of HC suggesting a potential role of SLF integrity in resilience to CBP. Structural connectivity-based models also classified SBPp and SBPr patients from the three data sets (validation accuracy 67%). Our results validate the right SLF as a robust predictor of CBP development, with potential for clinical translation. Cognitive and behavioral processes dependent on the right SLF, such as proprioception and visuospatial attention, should be analyzed in subacute stages as they could prove important for back pain chronicity.
-
- Neuroscience
To encode continuous sound stimuli, the inner hair cell (IHC) ribbon synapses utilize calcium-binding proteins (CaBPs), which reduce the inactivation of their CaV1.3 calcium channels. Mutations in the CABP2 gene underlie non-syndromic autosomal recessive hearing loss DFNB93. Besides CaBP2, the structurally related CaBP1 is highly abundant in the IHCs. Here, we investigated how the two CaBPs cooperatively regulate IHC synaptic function. In Cabp1/2 double-knockout mice, we find strongly enhanced CaV1.3 inactivation, slowed recovery from inactivation and impaired sustained exocytosis. Already mild IHC activation further reduces the availability of channels to trigger synaptic transmission and may effectively silence synapses. Spontaneous and sound-evoked responses of spiral ganglion neurons in vivo are strikingly reduced and strongly depend on stimulation rates. Transgenic expression of CaBP2 leads to substantial recovery of IHC synaptic function and hearing sensitivity. We conclude that CaBP1 and 2 act together to suppress voltage- and calcium-dependent inactivation of IHC CaV1.3 channels in order to support sufficient rate of exocytosis and enable fast, temporally precise and indefatigable sound encoding.
