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者。在第一个目标中，我们将探讨的假设，CaMK Ⅱ和磷酸酶-1（PP 1）在突触后致密（PSD）形成一个开关。将进行蒙特卡罗模拟。该模型将被用来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处小分子反应中随机波动的限制？在一组平行的生化实验中，我们将直接测试孤立的PSD中的CaMK II/PP 1系统是否可以作为一个开关。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。在去电位诱导过程中，中度Ca 2+升高通过涉及钙调神经磷酸酶、I1和PP 1的磷酸酶级联反应降低CaMKII磷酸化。由于<1%的突触在诱导过程中被激活，因此活性突触是点汇/源，产生可扩散分子（如I1）的树突梯度。这种梯度的建立可能解释诱导和异突触效应的动力学方面。由于梯度的作用以前没有考虑过，这将是有用的，使扩散模型来研究不同的因素如何影响空间/时间梯度的可塑性可能的重要性。在相关的生理实验中，我们将测试I1在去增强中的作用。目标3涉及最近的工作表明，LTP产生突触大小的稳定增加。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。模拟将用于探索可能构成结构稳定性的原理。这些目标共同解决了关于记忆在大脑中储存机制的最深层次问题。得出的见解可能是重要的理解疾病的记忆和建议的治疗干预策略。

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.