Shootin1a-Mediated Actin–Adhesion Coupling Generates Force to Trigger Structural Plasticity of Dendritic Spines

Dendritic spines constitute the major compartments of excitatory post-synapses. They undergo activity-dependent enlargement, which is thought to increase the synaptic efficacy underlying learning and memory. The activity-dependent spine enlargement requires activation of signaling pathways leading to promotion of actin polymerization within spines. However, the molecular machinery that suffices for this structural plasticity remains unclear. Here we demonstrate that shootin1a links polymerizing actin filaments in spines with the cell adhesion molecules N-cadherin and L1-CAM, thereby mechanically coupling the filaments to the extracellular environment. Synaptic activation enhances shootin1a-mediated actin–adhesion coupling in spines. Promotion of actin polymerization is insufficient for the plasticity: the enhanced actin–adhesion coupling is required for polymerizing actin filaments to push against the membrane for spine enlargement. By integrating cell signaling, cell adhesion, and force generation into the current model of actin-based machinery, we propose a molecular machinery that is sufficient to trigger the activity-dependent spine structural plasticity.

树突棘（dendritic spines）是兴奋性突触后结构的主要组成单元。它们可发生活动依赖性增大，这一过程被认为可增强支撑学习与记忆的突触效能。活动依赖性树突棘增大需要激活信号通路，以促进树突棘内的肌动蛋白聚合。然而，介导该结构可塑性的完整分子机制仍未阐明。本研究证实，shootin1a可将树突棘内正在聚合的肌动蛋白丝与细胞黏附分子N-钙粘蛋白（N-cadherin）和L1细胞黏附分子（L1-CAM）相连，从而将肌动蛋白丝与细胞外环境建立机械耦联。突触激活可增强树突棘内shootin1a介导的肌动蛋白-黏附耦联过程。仅促进肌动蛋白聚合并不足以实现该结构可塑性：正在聚合的肌动蛋白丝若要推动细胞膜以完成树突棘增大，必须依赖增强后的肌动蛋白-黏附耦联过程。我们将细胞信号转导、细胞黏附与力产生整合入当前基于肌动蛋白的机制模型，提出了一种可触发活动依赖性树突棘结构可塑性的完整分子机制。