CRCNS: Memory Mechanisms: Modifiability and Stability

描述(申请人提供)：CaMKII是分子存储器的领先候选者。在第一个目标中，我们将探索CaMKII和突触后密度(PSD)中的磷酸酶-1(PP1)形成双稳态开关的假设。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：突触上一小群分子的反应中的随机波动如何限制存储信息的稳定性？在一组平行的生化实验中，我们将直接测试分离的PSD中的CaMKII/PP1系统是否可以作为双稳开关。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调节。在诱导去增强的过程中，适度的钙升高通过涉及钙调神经磷酸酶、I1和PP1的磷酸酶级联反应来降低CaMKII的磷酸化。由于1%的突触在诱导过程中被激活，活性突触是点汇源，产生I1等可扩散分子的树枝状梯度。这种梯度的积累可以潜在地解释诱导和异突触效应的动力学方面。由于以前没有考虑到梯度的作用，所以建立扩散模型来研究不同因素如何影响塑性中可能重要的空间/时间梯度将是有用的。在相关的生理学实验中，我们将测试I1在去增强中的作用。目标3与最近的工作有关，该工作表明LTP能稳定增加突触大小。为了了解可能支撑这种结构稳定性的原理，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。模拟将被用来探索可能构成结构稳定性基础的原则。这些目标共同解决了关于记忆存储在大脑中的机制的最深层次的问题。得出的见解可能对理解记忆疾病并为治疗干预提供策略建议具有重要意义。

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.