CAM KINASE II AND LEARNING AND MEMORY

描述(摘自申请者摘要)：长期目标 这项研究旨在提供对分子基础的更清晰的理解 突触可塑性及其与学习、记忆和 行为。这是一个与健康相关的重要问题，因为异常 神经元功能已被认为与几种 疾病包括精神障碍，缺血性脑损伤，以及 阿尔茨海默氏症。这一系列研究也与年龄相关 记忆功能的变化。我们建议通过以下途径来研究这些机制 它是一种过度表达的钙非依赖性钙调蛋白依赖的激酶 II(CaMKII-Asp286)破坏海马区突触可塑性和 空间记忆依赖型任务的行为表现。我们的具体目标 是：(1)确定CaMKII-Asp286对钙调蛋白的捕获是否 足以产生观察到的生理和行为表型 小鼠表达这种钙非依赖形式的CaMKII，(2)确定是否 CaMKII-Asp286对大鼠脑内CA1区突触可塑性的影响 仅海马体就足以产生空间学习缺陷和 记忆，以及(3)识别学习和记忆的哪个阶段， 收购、整合或召回对中断非常敏感 转CaMKII-Asp286基因的表达。这些目标将会实现 通过研究CaMKII-Asp286的体外活性，通过创造两个新的 转基因小鼠品系，并通过测试这些和现有的转基因小鼠 空间任务中的动物。首先，我们计划创造一系列携带 一种不依赖于钙离子的CaMKII形式，它没有激酶活性，以便 确定单独捕获钙调蛋白是否可以产生类似于 在我们现有的老鼠身上看到了这一点。使用CRE-LOX系统，我们将创建一个 仅在CA1区表达CaMKII-Asp286的第二个小鼠系 海马体的。最后，我们计划研究的现有小鼠抑制 CaMKII-Asp286在四环素作用下的表达这将使我们能够 控制在得知转基因后的何时表达和 能够扰乱空间记忆。

DESCRIPTION (Adapted from applicant's abstract): The long-term objective of this research is to provide a clearer understanding of the molecular basis of synaptic plasticity and how this relates to learning, memory, and behavior. This is an important health-related issue because abnormal neuronal function has been implicated in the pathoetiology of several diseases including psychiatric disorders, ischemic brain injury, and Alzheimer's disease. This line of research is also relevant to age-related changes in memory function. We propose to study the mechanisms through which an overexpressed Ca2+-independent form of calmodulin-dependent kinase II (CaMKII-Asp286) disrupts both synaptic plasticity in the hippocampus and behavioral performance on spatial memory-dependent tasks. Our specific aims are (1) to determine whether calmodulin trapping by CaMKII-Asp286 is sufficient to produce the physiological and behavioral phenotype observed in mice expressing this Ca2+-independent form of CaMKII, (2) to determine if disruption of synaptic plasticity by CaMKII-Asp286 in the CA1 region of the hippocampus alone is sufficient to produce a deficit in spatial learning and memory, and (3) to identify which stage of learning and memory, either acquisition, consolidation, or recall, is sensitive to disruption by expression of the CaMKII-Asp286 transgene. These aims will be accomplished by studying the activity of CaMKII-Asp286 in vitro, by creating two new lines of transgenic mice, and by testing these and existing transgenic animals on spatial tasks. First, we plan to create a line of mice carrying a Ca2+-independent form of CaMKII that has no kinase activity in order to determine if calmodulin trapping alone can create a phenotype similar to that seen in our existing mice. Using the CRE-lox system, we will create a second line of mice which expresses the CaMKII-Asp286 only in the CA1 region of the hippocampus. Finally, the existing mice we plan to study suppress CaMKII-Asp286 expression in response to tetracycline. This will allow us to regulate at which time after learning the transgene is expressed and is capable of disrupting spatial memory.