Journal
CURRENT BIOLOGY
Volume 29, Issue 2, Pages 268-+Publisher
CELL PRESS
DOI: 10.1016/j.cub.2018.11.065
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Funding
- NIH [R01GM048661, R35 GM126950, F30NS092227]
- program Investissements d'Avenir''
- ANR [ANR-10-LBX-0038, ANR-10-IDEX-0001-02 PSL]
- Fondation pour la Recherche Medicale grant [DEQ20170336756]
- Fondation Vaincre Alzheimer grant [FR-16055p]
- NSF Science and Technology Center for Engineering MechanoBiology [CMMI-1548571]
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Neurons in the CNS establish thousands of en passant synapses along their axons. Robust neuro-transmission depends on the replenishment of synaptic components in a spatially precise manner. Using live-cell microscopy and single-molecule reconstitution assays, we find that the delivery of synaptic vesicle precursors (SVPs) to en passant synapses in hippocampal neurons is specified by an interplay between the kinesin-3 KIF1A motor and presynaptic microtubules. Presynaptic sites are hotspots of dynamic microtubules rich in GTP-tubulin. KIF1A binds more weakly to GTP-tubulin than GDP-tubulin and competes with end-binding (EB) proteins for binding to the microtubule plus end. A disease-causing mutation within KIF1A that reduces preferential binding to GDP- versus GTP-rich microtubules disrupts SVP delivery and reduces presynaptic release upon neuronal stimulation. Thus, the localized enrichment of dynamic microtubules along the axon specifies a localized unloading zone that ensures the accurate delivery of SVPs, controlling presynaptic strength in hippocampal neurons.
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