CAM KINASE II AND LEARNING AND MEMORY

描述（改编自申请人摘要）：长期目标 这项研究是为了更清楚地了解 突触可塑性以及它与学习、记忆和 行为 这是一个重要的健康相关问题，因为异常 神经元功能与几种神经系统疾病的病理学有关， 疾病，包括精神障碍、缺血性脑损伤和 老年痴呆症 这一系列的研究也与年龄有关。 记忆功能的变化。 我们建议研究的机制， 这是一种过表达的钙调蛋白依赖性激酶， II（CaMKII-Asp 286）破坏海马中的突触可塑性， 空间记忆相关任务的行为表现。 我们的具体目标 （1）确定CaMKII-Asp 286对钙调蛋白的捕获是否 足以产生在小鼠中观察到的生理和行为表型。 表达这种Ca 2+非依赖性形式的CaMKII的小鼠，（2）以确定是否 突触可塑性的破坏由CaMKII-Asp 286在CA 1区的 海马体本身就足以产生空间学习的缺陷， （3）确定学习和记忆的哪个阶段， 收购、整合或召回，对以下因素造成的破坏很敏感： CaMKII-Asp 286转基因的表达。 这些目标将会实现 通过研究CaMKII-Asp 286在体外的活性，通过创建两个新的 转基因小鼠，并通过测试这些和现有的转基因小鼠， 空间任务的动物。 首先，我们计划创造一系列携带 Ca 2+非依赖性形式的CaMKII，其没有激酶活性， 确定钙调蛋白捕获单独是否可以产生类似于 在我们现有的老鼠身上看到的。 使用CRE-lox系统，我们将创建一个 仅在CA 1区表达CaMKII-Asp 286的第二系小鼠 海马体的一部分。 最后，我们计划研究的现有小鼠抑制了 响应于四环素的CaMKII-Asp 286表达。 这将使我们能够 调节在学习后转基因表达的时间， 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.