Synaptopodins Role in Synaptic Plasticity and Neuronal Circuitry

神经元之间的连接被称为突触，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。突触网络在发育过程中的适应以及对损伤或学习的反应是通过突触形成和消除的连续过程发生的。至少有两种不同的机制在这些过程中发挥着核心作用：一种是通过活动依赖的机制选择性地稳定突触，另一种是修改突触的周转和动力学，以允许网络重新连接。突触结构可塑性的这些不同方面背后的分子机制仍然很大程度上是未知的。我的团队一直在研究某些突触稳定而其他突触更具可塑性的机制。在中枢神经系统中，大多数兴奋性突触包含在称为树突的树突中，树突具有不同的形状和突触强度。脊椎可以将突触传递的部位与树突干分开，树突干允许突触特定的输入和信号处理。除了脊柱形状的明显变化外，细胞内成分的分布是不均匀的，可以影响脊柱对可塑性诱导刺激的功能反应和形态重塑。有趣的是，大脑中的一组脊椎包含一个以内质网(ER)为基础的复杂细胞器，称为脊器(SA)。SA通常定位于脊柱颈部或脊柱头部底部，由夹杂电子致密板的片状内质网组成，连接到主要的内质网，并与突触素、肌动蛋白结合蛋白和SA的标记共同定位。这种结构作为钙储存库，对于NMDA依赖的突触可塑性和齿状回内稳态伸缩(机制未知)是重要的。SA含有突触蛋白。因此，SA和突触素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，目前仍不清楚突触素是否参与调节其他突触或突触可塑性的其他方面，如突触重新连接以及机制如何。在这项发现拨款中，我们将建立在初步数据和内部工具的基础上，以确定突触素如何阻止内稳态伸缩，以及它是否参与了其他形式的可塑性。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。该方案将允许3名研究生学习先进的光学、电生理和生化技术，1名本科生学习成像、重建和蛋白质印迹，从而为HQP的培训提供了理想的环境。

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.