Synaptopodins Role in Synaptic Plasticity and Neuronal Circuitry

神经元之间的连接称为突触，旨在快速有效地将信号从一个神经元传递到另一个神经元。这种连接需要稳定，以便保存重要信息，同时具有足够的灵活性来容纳新信息。在发育过程中以及对损伤或学习的响应中，突触网络的适应通过突触形成和消除的连续过程发生。至少有两种不同的机制在这些过程中发挥了核心作用：一个涉及通过活动依赖性机制选择性稳定突触，第二个涉及修改突触周转和动态，以允许网络重新布线。突触结构可塑性的这些不同方面的分子机制仍然是未知的。我的团队一直在研究为什么某些突触是稳定的，而另一些突触更具可塑性。在中枢神经系统中，大多数兴奋性突触包含在称为树突棘的树突突起内，树突棘具有不同的形状和突触强度。棘允许将突触传递的位点与树突轴分离，这允许突触特异性输入和信号处理。除了脊柱形状的明显变化之外，细胞内成分是不均匀分布的，并且可以影响脊柱如何在功能上对可塑性诱导刺激做出反应并在形态上重塑。有趣的是，大脑中的棘亚群包含一个复杂的基于内质网（ER）的细胞器，称为棘器（SA）。SA通常位于脊柱颈部或脊柱头部的基部，由层状ER堆叠和居间的电子致密板组成，连接到主要的ER网络，并与突触足蛋白（synaptopodin）共定位，突触足蛋白是肌动蛋白结合蛋白和SA的标记物。该结构作为钙储存，并且对于NMDA依赖的突触可塑性和齿状回的稳态缩放是重要的（机制未知）。SA含有蛋白质synaptopodin。总之，SA和突触足蛋白的存在或缺失可以深刻地影响脊柱对突触传递的反应。然而，目前尚不清楚突触足蛋白是否参与缩放其他突触或突触可塑性的其他方面，如突触重新布线及其机制。在这项发现补助金中，我们将建立在初步数据和内部工具的基础上，以确定突触足蛋白如何防止稳态缩放，以及它是否涉及其他形式的可塑性。这项研究计划将阐明管理信息存储和神经元电路重新布线的规则。该项目将允许3名研究生学习先进的光学、电生理和生物化学技术，一名本科生学习成像、重建和蛋白质印迹，从而为培养HQP提供理想的环境。

The connections between neurons, called synapses, are designed to rapidly and efficiently relay signals from one neuron to another. Such connections need to be stable in order to preserve important information while at the same time have enough flexibility to accommodate new information. Adaptation of synaptic networks during development and in response to injury or learning occurs through a continuous process of synapse formation and elimination. At least two distinct mechanisms play a central role in these processes: one involves a selective stabilization of synapses through activity-dependent mechanisms and a second involves modifications of synapse turnover and dynamics to allow network rewiring. The molecular mechanisms underlying these different aspects of synaptic structural plasticity are still largely unknown. My team have been investigating the mechanisms involved in why certain synapses are stable while others are more plastic. In the central nervous system, the majority of excitatory synapses are contained within dendritic protrusions called dendritic spines that have different shapes and synaptic strengths. The spines permit separation of the site of synaptic transmission from the dendritic shaft, which allows synapse-specific inputs and signal processing. Beyond the obvious variation of spine shape, intracellular components are heterogeneously distributed and can influence how a spine will functionally respond to plasticity-inducing stimuli and remodel morphologically. Interestingly a subset of spines within  the brain contains a complex endoplasmic reticulum (ER)-based organelle called the spine apparatus (SA). The SA is usually localized in the spine neck or at the base of the spine head and consists of laminar ER stacks with intervening electron-dense plates, connected to the main ER network and colocalizes with synaptopodin, an actin-binding protein and a marker for the SA. This structure serves as a calcium store, and is important for NMDA-dependent synaptic plasticity and homeostatic scaling in of the dentate gyrus (mechanism unknown). The SA contains the protein synaptopodin. Together, the presence or absence of the SA and synaptopodin can thus profoundly affect how a spine will react to synaptic transmission. However, it is still unclear if synaptopodin is involved in scaling other synapses or other facets of synaptic plasticity, such as synapse rewiring and what the mechanism. In this Discovery Grant we will build on preliminary data and in house tools to determine how synaptopodin prevents homeostatic scaling and if it is involved on other forms of plasticity. This research program will clarify the rules that govern information storage and rewiring of neuronal circuitry. The proposal will allow 3 graduate students to learn advanced optical, electrophysiology and biochemical techniques, and an undergraduate to learn imaging, reconstruction and western blotting, thus providing an ideal setting for the training of HQP.