Deciphering the molecular mechanisms of cyclase-associated protein 1 (CAP1) in regulating dendritic spine morphology and structural plasticity

肌动蛋白细丝(F-肌动蛋白)决定树突棘的形态，树突棘是大脑中大多数兴奋性突触的突触后间隔。由F-肌动蛋白组装和分解引起的活动诱导的脊柱形态变化(称为结构可塑性)支持突触可塑性，并与学习和记忆等脑功能相关。因此，控制F-肌动蛋白动态的肌动蛋白结合蛋白(ABP)作为突触生理、脑功能和行为的关键调节因子进入了焦点。我们和其他人的研究发现，ADF/cofilin家族的ABP是脊椎F-肌动蛋白动态的关键调节因子。此外，这些研究表明，对脊柱中cofilin 1活动的严格调控对于正常的突触功能是强制性的，并且cofilin 1的失调导致了与人类神经精神障碍相关的细胞和行为缺陷。我们未发表的数据表明，环化酶相关蛋白1(Cap1)是脊柱中一种新的肌动蛋白调节因子，与脊柱形态和结构可塑性有关。此外，它们还证明了cap1和cofilin1在调节脊柱形态方面的功能相互依赖。Cap1包含几个保守的蛋白结构域，推测除了肌动蛋白和Cofilin1外，这些结构域可能还允许与各种蛋白质相互作用。因此，我建议Cap1在脊椎中扮演分子枢纽的角色，与包括cofilin1在内的各种相互作用因子的活动相关，并且上游调控机制作用于Cap1，以控制脊椎中F-肌动蛋白动态的机制。这项拟议的项目旨在寻找与Cap1功能及其与脊椎中cofilin1相互作用相关的新的突触Cap1相互作用伙伴。从我们的建议中，我们期待着对控制突触F-肌动蛋白动力学、脊柱形态和结构可塑性的机制有重要的新见解。

Actin filaments (F-actin) determine the morphology of dendritic spines, the postsynaptic compartment of most excitatory synapses in the brain. Activity-induced spine morphological changes (termed structural plasticity) caused by F-actin assembly and disassembly supports synaptic plasticity and is relevant for brain functions like learning and memory. Hence, actin-binding proteins (ABP) that control F-actin dynamics moved into the focus as critical regulators of synapse physiology, brain function and behavior. Studies from us and others identified ABP of the ADF/cofilin family as key regulators of F-actin dynamics in spines. Moreover, these studies revealed that a tight regulation of cofilin1 activity in spines is mandatory for proper synapse function and that cofilin1 dysregulation caused cellular and behavioral deficits associated with human neuropsychiatric disorders. Our unpublished data identified cyclase-associated protein 1 (CAP1) as a novel actin regulator in spines that is relevant for spine morphology and structural plasticity. Moreover, they demonstrated functional interdependence of CAP1 and cofilin1 in regulating spine morphology. CAP1 contains several conserved protein domains that presumably allow interaction with a variety of proteins apart from actin and cofilin1. I therefore propose that CAP1 acts as a molecular hub in spines relevant for the activity of various interactors including cofilin1 and that upstream regulatory mechanisms act on CAP1 to control the machinery that governs F-actin dynamics in spines. The proposed project is designed to identify novel synaptic CAP1 interaction partners that are relevant for CAP1 function and its interaction with cofilin1 in spines. From our proposal we expect important novel insights into the mechanisms that control synaptic F-actin dynamics, spine morphology and structural plasticity.