A kinesin 1-protrudin complex mediates AMPA receptor synaptic removal during long-term depression
The synaptic removal of AMPA-type glutamate receptors (AMPARs) is a core mechanism for hippocampal long-term depression (LTD). In this study, we address the role of microtubule-dependent transport of AMPARs as a driver for vesicular trafficking and sorting during LTD. Here, we show that the kinesin-1 motor KIF5A/C is strictly required for LTD expression in CA3-to-CA1 hippocampal synapses. Specifically, we find that KIF5 is required for an efficient internalization of AMPARs after NMDA receptor activation. We show that the KIF5/AMPAR complex is assembled in an activity-dependent manner and associates with microsomal membranes upon LTD induction. This interaction is facilitated by the vesicular adaptor protrudin, which is also required for LTD expression. We propose that protrudin links KIF5-dependent transport to endosomal sorting, preventing AMPAR recycling to synapses after LTD induction. Therefore, this work identifies an activity-dependent molecular motor and the vesicular adaptor protein that executes AMPAR synaptic removal during LTD. ; Spanish Ministry of Science (SAF2017-86983-R, PID2020-117651RB) to J.A.E. A.L., Y.G., and A.F.-R. were recipients of predoctoral contracts from the Spanish Ministry of Science. A.B. was funded by the European Union (Marie Curie Intra-European Fellowship program). F.F.H. was funded by the Deutsche Forschungsgemeinschaft (DFG) project 416580360 and HE8413/1-1 and by the Ritz-Stiftung. M.K. was funded by the DFG grants FOR2419 project KN556/11-1 and KN556/11-2
