Modeling of Calcium Dynamics in Spines

该项目的长期目标是开发一个模型来解释用于诱导长期增强（LTP）和长期抑制（LTD）的配对协议中涉及的关键时间窗口。这将需要对树突棘中的树突Ca2+动力学进行详细分析，并对神经活动引发的Ca2+介导的信号转导级联进行研究。该模型将借鉴本提案中关于脊柱结构和重要分子位置的其他项目的实验数据（项目2:Weinberg）， Ca 2+流入后脊柱中发生的生化反应（项目3:Kennedy）以及使用双光子显微镜直接测量Ca 2+动力学（项目4:Svoboda）。这些测量结果将被纳入蒙特卡洛meli

The long-term goal of this project is to develop a model to explain the critical time window involved in the pairing protocol used for the induction of long-term potentiation (LTP) and long-term depression (LTD). This will require a detailed analysis of dendritic Ca 2+ dynamics in dendritic spines and an investigation of the Ca2+-mediated signal transduction cascades initiated by neural activity. The model will draw on experimental data from the other projects in this proposal on the structure of the spine and the location of important molecules (Project 2: Weinberg), the biochemical reactions that occur in the spine following the influx of Ca 2+ (Project 3: Kennedy) and the direct measurements of Ca 2+ dynamics using 2-photon microscopy (Project 4: Svoboda). These measurements will be incorporated into MCelI, a Monte Carlo computer program that simulates subcellular signaling by following the random walk and interactions between diffusible molecules. Three specific aims will be pursued in parallel. First a 5 _mx 5 _m ? 5 _m volume of hippocampal area CA1 neuropil from mouse will be reconstructed to serve as the anatomical substrate of the simulations. This will allow simulations of neurotransmitter release and diffusion in the extracellular space to be accurately modeled. Second, we will use the model to estimate [Ca 2+] in small functional microdomains, such as in the postsynaptic density. Since the reconstruction will likely contain around 100 spines of varying shapes and sizes, we will also obtain estimates of variability in the system. The model will be able to measure the activation of calmodulin (CAM) following an EPSP, an action potential, or both occurring with a temporal offset, and to then allow activated CaM to bind to, and activate CaMKII. Third, we will examine theoretically how much variability is expected to result from the stochastic schemes implemented by MCell to determine how many simulation runs will be needed to obtain accurate estimates. We will develop an analytical approximation to the stochastic model to determine the statistical distribution of system dynamics. In preliminary studies, we used computer simulation of receptor activation and calcium dynamics at glutamatergic synapses in a simplified model of a segment of dendrite with dendritic spine and PSD. Since this signal transduction cascade implies interactions between multiple diffusible species, the new modeling capabilities for MCell proposed in Core Facility 1 are prerequisite to this project.