Calmodulin's Role in Synaptic Plasticity: A Computational Approach

树突棘是哺乳动物大脑中兴奋性神经传递的主要部位，是形态上可识别的小结构。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的信息处理是至关重要的。脊椎是相互隔离的生化隔间，使每个脊椎都能作为一个独立的生化单位发挥作用。脊椎也是突触可塑性的部分诱导和维持的部位，通过激活精心安排的一整套 改变突触功能的酶。在大多数突触可塑性模型中，关键是细胞内钙离子的增加在诱导长期功能变化中的作用，脊椎已经进化出独特的机制来精细地控制钙信号的时间和数量性质。然而，这种单一的第二信使如何被用来产生与长期增强或长期抑郁一样截然不同的反应尚不清楚。我们认为，钙调蛋白在决定钙信号如何被脊柱的生化装置解码中起着关键作用。更具体地说，我们假设之前未被认识到的钙依赖和钙依赖 独立的钙调蛋白-靶相互作用负责对钙信号进行解码。我们建议通过应用计算策略来测试这些想法。实现三个具体目标。首先，基于从体外实验中收集的生物物理和酶数据，将构建钙/钙调蛋白信号通路的详细模型。这将使我们能够研究钙调蛋白-靶相互作用在解码混合良好的隔室中的钙信号中的重要作用。其次，将构建一个蒙特卡罗计算机模拟来模拟CaM和目标蛋白之间的分子相互作用，这些分子相互作用正在脊柱细胞质的非均质模型中进行扩散。这种新颖的模拟是基于和指导正在进行的钙调素-靶蛋白相互作用的体外和体内荧光光谱数据。第三，模拟将扩展到包含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钙是如何- 脊髓中信号驱动的钙调蛋白-靶相互作用在空间和时间上被编排，并将它们的激活与不同形式的突触可塑性(例如，峰时依赖的可塑性、LTP和LTD)相关联。这项研究的长期目标是建立一个脊柱的计算模型，可以用来研究有关酶网络信息处理能力的假设，这些假设受已知的结构、生化和生物物理数据的约束。

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.