Regulation of structural plasticity and actin cytoskeleton by plasma membrane cholesterol turnover in dendritic spines

树突棘质膜胆固醇周转对结构可塑性和肌动蛋白细胞骨架的调节

• 批准号: RGPIN-2018-05562
• 负责人: Karten, Barbara
• 金额: $ 2.62万
• 依托单位: Dalhousie University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=713124
• 关键词: Regulation; structural; plasticity; actin; cytoskeleton

All cells are surrounded by a membrane of lipids and proteins that controls the cell's interaction with the environment. The membrane rapidly adjusts to the environment and the cell's needs by changing its composition and shape. Cholesterol is an essential component of all animal membranes and regulates their flexibility, permeability and other characteristics. Our research program focuses on cholesterol in nerve cell membranes. We investigate how cholesterol levels in the membrane are regulated and how changes in membrane cholesterol levels influence nerve cell communication. Nerve cells have a very intricate shape which is optimized to connect with many other nerve cells to form a large communication network in the brain. To be able to receive input from many other cells, nerve have long, branched processes called dendrites, which have additional small membrane protrusions called dendritic spines. At the tip of these spines, the nerve cell connects with another nerve cell to receive a signal. One neuron has many dendrites, each with many spines, so each neuron can receive input from with many other nerve cells. The number of spines and their size influence the strength of the incoming signal. Nerve cells can rapidly adjust the shape of the spines according to an incoming signal. This process is called synaptic plasticity and is the basis for learning and memory. Other studies have shown that nerve cells release cholesterol from the membrane when they receive strong signals from other cells, and later recover that cholesterol. However, it is not known how the initial release affects the shape and function of the spines, and it is not known how nerve cells quickly regain cholesterol after having released it; they could take it up from surrounding support cells or make it themselves. We aim to address these questions by culturing nerve cells in the presence of their normal support cells, and experimentally induce defects in cholesterol release or in the production of cholesterol inside nerve cells. We will then characterize the effects of these changes on the size and number of dendritic spines, and determine whether they can still adjust to incoming signals. We also aim to determine how cholesterol content in the spines changes during nerve cell activity. Preliminary experiments suggest that spine growth in response to signals is impaired when cholesterol production is disrupted, even though the nerve cells can still get cholesterol from outside. We aim to elucidate the mechanisms through which how cholesterol influences the spine, and why external cholesterol may not be able to fully replace external cholesterol coming from the other cells. Our work addresses a fundamental aspect of nerve cell function. Moreover, given that nerve cells are not the only cells that change their shape rapidly in response to signals, some of these mechanisms may also be important in other cell types.

所有的细胞都被一层由脂质和蛋白质组成的膜包围着，这些膜控制着细胞与环境的相互作用。细胞膜通过改变其组成和形状来迅速适应环境和细胞的需要。胆固醇是所有动物细胞膜的重要组成部分，并调节其柔韧性、渗透性和其他特性。我们的研究项目集中在神经细胞膜中的胆固醇。我们研究了膜内胆固醇水平是如何被调节的，以及膜内胆固醇水平的变化是如何影响神经细胞通讯的。神经细胞具有非常复杂的形状，可以与许多其他神经细胞相连接，在大脑中形成一个巨大的通信网络。为了能够接收来自许多其他细胞的输入，神经有长长的分支过程，称为树突，它有额外的小膜突起，称为树突棘。在这些棘的尖端，神经细胞与另一个神经细胞连接以接收信号。一个神经元有许多树突，每个树突都有许多棘，所以每个神经元可以接受来自许多其他神经细胞的输入。棘的数量和大小影响输入信号的强度。神经细胞可以根据接收到的信号迅速调整脊髓的形状。这个过程被称为突触可塑性，是学习和记忆的基础。其他研究表明，当神经细胞接收到来自其他细胞的强烈信号时，它们会从细胞膜上释放胆固醇，然后再恢复这些胆固醇。然而，目前尚不清楚最初的释放如何影响脊柱的形状和功能，也不清楚神经细胞在释放胆固醇后如何迅速恢复胆固醇；它们可以从周围的支持细胞中获取，也可以自己制造。我们的目标是通过在正常支持细胞存在的情况下培养神经细胞来解决这些问题，并通过实验诱导胆固醇释放或神经细胞内胆固醇产生的缺陷。然后，我们将描述这些变化对树突棘大小和数量的影响，并确定它们是否仍能适应输入信号。我们还旨在确定在神经细胞活动期间脊柱中的胆固醇含量是如何变化的。初步实验表明，尽管神经细胞仍然可以从外界获取胆固醇，但当胆固醇的产生被破坏时，脊柱对信号的反应会受到损害。我们的目的是阐明胆固醇如何影响脊柱的机制，以及为什么外部胆固醇可能不能完全取代来自其他细胞的外部胆固醇。我们的工作涉及神经细胞功能的一个基本方面。此外，考虑到神经细胞并不是唯一能根据信号迅速改变形状的细胞，其中一些机制可能对其他类型的细胞也很重要。