Abstract Dendritic spines of excitatory neurons undergo activity-dependent structural and functional plasticity, which are cellular correlates of learning and memory. However, mechanisms underlying the rapid morphological changes immediately after NMDAR-mediated Ca 2+ influx into spines remain poorly understood. Here we report that endophilin A1, a neuronal N-BAR protein, orchestrates membrane dynamics with actin polymerization to initiate spine enlargement in the induction phase of long-term potentiation (LTP). Upon LTP induction, Ca 2+ /calmodulin enhances its binding to both membrane and p140Cap, a cytoskeleton regulator. As a result, endophilin A1 rapidly associates with the relaxed plasma membrane and promotes actin polymerization, leading to acute expansion of spine head. Moreover, not only the p140Cap-binding, but also calmodulin- and membrane-binding capacities of endophilin A1 are required for LTP and long-term memory. Thus, endophilin A1 functions as calmodulin effector to drive spine enlargement in response to Ca 2+ influx in the initial phase of structural plasticity.

Endophilin A1 promotes Actin Polymerization in response to Ca2+/calmodulin to Initiate Structural Plasticity of Dendritic Spines