Calmodulin's Role in Synaptic Plasticity: A Computational Approach

钙调蛋白在突触可塑性中的作用：一种计算方法

• 批准号: 6995173
• 负责人: M. NEAL WAXHAM
• 金额: $ 17.57万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6995173
• 关键词: calcium flux; calmodulin; computational neuroscience; computer simulation; dendrites; fluorescence spectrometry; neural plasticity; protein protein interaction

Dendritic spines are small morphologically identifiable structures that are the major sites where excitatory neurotransmission occurs in the mammalian brain. Thorough knowledge of their structure and function are critical for understanding information processing in the nervous system at the cellular level. Spines are well isolated biochemical compartments permitting each spine to function as an independent biochemical unit. Spines are also the site where synaptic plasticity is in part induced and maintained via the activation of well-orchestrated sets of enzymes that modify synaptic function. Critical in most models of synaptic plasticity is the role of increased intracellular Ca2+ in inducing long-term functional changes and spines have evolved unique mechanisms to finely control the temporal and quantitative nature of the Ca2+-signal. However, how this single second messenger is used to produce responses as distinct as long-term potentiation or long-term depression is not clear. We propose that calmodulin serves a critical role in determining how Ca2+ signals are decoded by the spine's biochemical apparatus. More specifically, we hypothesize that previously unrecognized Ca2+-dependent and Ca2+- independent calmodulin-target interaction are responsible for decoding the Ca2+-signal. We propose to test these ideas by applying a computational strategy. Three specific aims will be accomplished. First, detailed models will be constructed of the Ca2+/calmodulin signaling pathway based on biophysical and enzymatic data collected from in vitro experiments. This will allow us to investigate an important role of calmodulin-target interaction in decoding Ca2+ signals in a well-mixed compartment. Second, a Monte Carlo computer simulation will be constructed to model molecular interaction between CaM and target protein that are undergoing diffusion in a non-homogenous model of spine cytoplasm. This novel simulation is based on and guided by on-going in vitro as well as in vivo fluorescence spectroscopic data of calmodulin-target protein interactions. Third, the simulation will be extended to incorporate geometric boundaries and spatial constraints of the dendritic spine. This model will allow us to explore how Ca2+- signal driven calmodulin-target interactions in the spine are orchestrated in space and time and to correlate their activation with different forms of synaptic plasticity (e.g., spike-timing dependent plasticity, LTP and LTD). The long-term goal of the studies is to establish a computational model of a spine that can be used to investigate hypotheses concerning the information processing capabilities of enzymatic networks constrained by known structural, biochemical and biophysical data.

树突棘是哺乳动物大脑中兴奋性神经传递发生的主要场所。彻底了解它们的结构和功能对于在细胞水平上理解神经系统中的信息处理至关重要。棘是很好地隔离的生化隔室，允许每个棘作为一个独立的生化单位发挥作用。脊髓也是突触可塑性部分通过激活精心编排的神经元而被诱导和维持的部位。 改变突触功能的酶。在大多数突触可塑性模型中，细胞内Ca 2+增加在诱导长期功能变化中的作用至关重要，并且棘已经进化出独特的机制来精细地控制Ca 2+信号的时间和定量性质。然而，这个单一的第二信使是如何被用来产生像长时程增强或长时程抑制这样独特的反应的，目前还不清楚。我们建议，钙调蛋白在确定如何钙信号是由脊柱的生化装置解码的关键作用。更具体地说，我们假设以前未被认识到的Ca 2+依赖性和Ca 2 +-依赖性， 独立的钙调素-靶相互作用负责解码Ca 2+信号。我们建议通过应用计算策略来测试这些想法。将实现三个具体目标。首先，详细的模型将构建的钙/钙调蛋白信号通路的基础上，从体外实验中收集的生物物理和酶的数据。这将使我们能够研究钙调素靶相互作用在解码Ca 2+信号中的重要作用。其次，将构建Monte Carlo计算机模拟来模拟在非均质脊柱细胞质模型中进行扩散的CaM和靶蛋白之间的分子相互作用。这种新的模拟的基础上，并指导正在进行的体外以及在体内的荧光光谱数据的钙调素靶蛋白相互作用。第三，模拟将被扩展到包括树突棘的几何边界和空间约束。这个模型将使我们能够探索Ca 2 +- 脊柱中信号驱动的钙调蛋白-靶相互作用在空间和时间上被协调并且使它们的激活与不同形式的突触可塑性相关（例如，发放时间依赖性可塑性、LTP和LTD）。这些研究的长期目标是建立一个脊柱的计算模型，该模型可用于研究受已知结构，生物化学和生物物理数据约束的酶网络信息处理能力的假设。