CRCNS: Memory Mechanisms: Modifiability and Stability

描述（由申请人提供）：CaMKII是分子记忆的主要候选药物。在第一个目标中，我们将探索CaMKII和磷酸酶-1 （PP1）在突触后密度（PSD）中形成双稳态开关的假设。蒙特卡罗模拟将被开发。该模型将用于解决一个基本的理论问题：存储信息的稳定性如何受到突触上小分子反应的随机波动的限制？在一组平行的生化实验中，我们将直接测试孤立psd中的CaMKII/PP1系统是否可以作为双稳态开关。在目标2中，我们研究了突触强度如何通过不同的突触激活模式进行双向修改。在诱导去增强过程中，适度的Ca2+升高通过磷酸酶级联降低CaMKII磷酸化，包括钙调磷酸酶、I1和PP1。由于小于1%的突触在诱导过程中被激活，活跃的突触是点汇/源，产生扩散分子（如I1）的树突梯度。这种梯度的形成可能解释诱导和异突触效应的动力学方面。由于之前没有考虑到梯度的作用，因此建立一个扩散模型来研究不同因素如何影响在塑性中可能重要的时空梯度将是有用的。在相关的生理实验中，我们将测试I1在去强化中的作用。Aim 3与最近的研究表明LTP产生突触大小的稳定增加有关。为了理解这种结构稳定性背后的原理，我们组建了一个拥有物理化学、结构生物学、神经科学和物理学专业知识的团队。模拟将用于探索结构稳定性背后的原理。这些目标共同解决了记忆在大脑中储存的机制这一最深刻的问题。所得的见解可能对理解记忆疾病具有重要意义，并为治疗干预提供策略建议。

DESCRIPTION (provided by applicant): CaMKII is a leading candidate as a molecular memory. In a first aim, we will explore the hypothesis that CaMKII and phosphatase-1 (PP1) in the postsynaptic density (PSD) form a bistable switch. Monte Carlo simulations will be developed. The model will be used to address a fundamental theoretical question: how is the stability of stored information limited by stochastic fluctuations in the reactions of the small group of molecules at synapses? In a parallel set of biochemical experiments, we will directly test whether the CaMKII/PP1 system in isolated PSDs can act as a bistable switch. In Aim 2 we examine how synaptic strength can be bi-directionally modified by different patterns of synaptic activation. The moderate Ca2+ elevation during the induction of depotentiation reduces CaMKII phosphorylation through a phosphatase cascade that involves calcineurin, I1 and PP1. Since <1% of synapses are activated during induction active synapses are point sinks/sources, producing dendritic gradients of diffusible molecules such as I1. The buildup of such gradients could potentially explain kinetic aspects of induction and heterosynaptic effects. Because the role of gradients has not been previously considered, it will be useful to make a diffusion model to study how different factors affect the spatial/temporal gradient of possible importance in plasticity. In related physiological experiments, we will test the role of I1 in depotentiation. Aim 3 relates to recent work indicating that LTP produces a stable increase in synapse size. To understand the principles that might underlie such structural stability, we have formed a team with expertise in physical chemistry, structural biology, neuroscience and physics. Simulations will be used to explore the principles that could underlie structural stability. Together these aims address the deepest issues regard the mechanism by which memories are stored in the brain. The insights derived are likely to be of importance in understanding diseases of memory and suggest strategies for therapeutic intervention.