Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, Department of Neuroscience, University of Torino, 10126 Torino, Italy, Institute of Neuroscience of the National Research Council of Italy, 56124 Pisa, Italy, Department of Neuroscience, Psychology, Drug Research and Child Health (Neurofarba), University of Florence, 50135 Florence, Italy, National Institute of Neuroscience-Italy, 10125 Torino, Italy, Department of Biotechnology and Translational Medicine, University of Milan, and Humanitas Clinical and Research Center, Rozzano, 20089 Milan, Italy, and Institute of Anatomy and Molecular Neurobiology, Westfälische Wilhelms-University, D-48149 Münster, Germany.
J Neurosci. 2014 Jan 22;34(4):1542-53. doi: 10.1523/JNEUROSCI.2341-13.2014.
A major challenge in the neuroscience field is the identification of molecules and pathways that control synaptic plasticity and memory. Dendritic spines play a pivotal role in these processes, as the major sites of excitatory synapses in neuronal communication. Previous studies have shown that the scaffold protein p140Cap localizes into dendritic spines and that its knockdown negatively modulates spine shape in culture. However, so far, there is no information on its in vivo relevance. By using a knock-out mouse model, we here demonstrate that p140Cap is a key element for both learning and synaptic plasticity. Indeed, p140Cap(-/-) mice are impaired in object recognition test, as well as in LTP and in LTD measurements. The in vivo effects of p140Cap loss are presumably attenuated by noncell-autonomous events, since primary neurons obtained from p140Cap(-/-) mice show a strong reduction in number of mushroom spines and abnormal organization of synapse-associated F-actin. These phenotypes are most likely caused by a local reduction of the inhibitory control of RhoA and of cortactin toward the actin-depolymerizing factor cofilin. These events can be controlled by p140Cap through its capability to directly inhibit the activation of Src kinase and by its binding to the scaffold protein Citron-N. Altogether, our results provide new insight into how protein associated with dynamic microtubules may regulate spine actin organization through interaction with postsynaptic density components.
神经科学领域的一个主要挑战是识别控制突触可塑性和记忆的分子和途径。树突棘在这些过程中起着关键作用，因为它们是神经元通讯中兴奋性突触的主要部位。先前的研究表明，支架蛋白 p140Cap 定位于树突棘，其敲低会在培养物中负调节棘突形状。然而，到目前为止，还没有关于其体内相关性的信息。通过使用敲除小鼠模型，我们在这里证明 p140Cap 是学习和突触可塑性的关键因素。事实上，p140Cap(-/-) 小鼠在物体识别测试、LTP 和 LTD 测量中受损。p140Cap 缺失的体内效应可能被非细胞自主事件减弱，因为从 p140Cap(-/-) 小鼠获得的原代神经元显示蘑菇棘突数量明显减少和突触相关 F-肌动蛋白的异常组织。这些表型很可能是由于 RhoA 和肌动蛋白解聚因子胞质蛋白的抑制性控制的局部减少以及它们与肌动蛋白结合蛋白 Citron-N 的相互作用所致。总之，我们的结果提供了新的见解，即与动态微管相关的蛋白质如何通过与突触后密度成分相互作用来调节棘突肌动蛋白组织。
