2023
eLife

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

Authors:

Hélène Vitet, Julie Bruyère, Hao Xu, Claire Séris, Jacques Brocard, Yah-Sé Abada, Benoît Delatour, Chiara Scaramuzzino, Laurent Venance, Frédéric Saudou

Keywords:

neurotransmitters, synapse, synaptic vesicles, Huntingtin protein, axonal transport, synaptic plasticity

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.