Heterogeneous and specific localization of mRNAs at dendritic spine and its dependence on microtubule entry

ABSTRACT Local mRNA translation near neuronal synapses is crucial for structural plasticity during brain development and memory formation. Whereas mRNAs are transported from soma to dendrites as individual ribonucleoprotein (RNP) granules, how do they subsequently localize at synapses is unclear. In particular, whether different dendritic mRNAs might display differential synaptic localization and interact with specific postsynaptic proteins remains unexplored. Here we found that two well-known dendritic mRNAs, Actb and Camk2a, are targeted to different subdomains of dendritic spines and delivered to different spine populations after synaptic stimulation. Surprisingly, the induced mRNA localization to dendritic spines is associated with microtubule (MT) entry and specifically requires the MT-associated motor KIF5A. Proximity-labelling proteomics further identifies distinct postsynaptic proteins enriched by Actb and Camk2a , from which we uncover the cytoskeletal protein Septin7 to be co-localized with the two mRNAs at different subdomains of dendritic spines. Our study reveals an unexpectedly specific mRNA localization mechanism at synapses and demonstrates proximity-labelling as a useful approach to map their synaptic partners.