DEFINING THE ROLE OF CAMKII IN SYNAPTIC PLASTICITY

定义 CAMKII 在突触可塑性中的作用

• 批准号: 6322293
• 负责人: ROBERTO MALINOW
• 金额: $ 5万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-01 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6322293
• 关键词: AMPA receptors; biological signal transduction; calmodulin dependent protein kinase; dendrites; enzyme activity; exocytosis; genetically modified animals; hippocampus; laboratory mouse; laboratory rat; long term potentiation; mutant; nerve /myelin protein; neural transmission; synapses

A promising and widely studied example of vertebrate synaptic plasticity is long-term potentiation (LTP), the persistent synaptic enhancement seen following a brief period of coincident pre- and postsynaptic activity. It has been suggested that the cellular and molecular mechanisms responsible for LTP will elucidate physiological and pathological phenomena including learning, memory, developmental synapse specificity, pain, neuronal death, epilepsy and dementia. The cellular signaling responsible for generating LTP has been studied extensively. Previous studies indicate that calcium/calmodulin-dependent protein kinase II (CaMKII) is both necessary and sufficient to produce LTP and thus may mediate the formation of memories. Here we will examine cellular and molecular consequences of increased CaMKII activity that may contribute to LTP. The central hypothesis to be tested is that increased postsynaptic CaMKII activity increases the number of AMPA receptors at excitatory synapses: both at synapses containing and not containing AMPA receptors. This will be examined with several complementing methodologies including electrophysiology, two photon imaging of GFP-tagged receptors, and immunohistochemistry with light and electron microscopy. These studies will use rodent hippocampal slices (acute and organotypic) and dissociated cultured neurons. A primary motivation to understand the cellular signaling responsible for learning and memory is to understand and alleviate diseases affecting these functions. Toward this goal, we will examine LTP and the role of CaMKII in transgenic mice expressing mutant PS-1, a protein strongly linked to Alzheimer's disease. This protein perturbs calcium homeostasis and our preliminary data show these mice have abnormally large LTP. SA1: To determine the mechanism(s) by which CaMKII increases synaptic AMPA-receptor function. SA2: To determine if CaMKII converts silent synapses into functioning synapses. SA3: To determine if dendritic exocytosis plays a role in LTP. SA4: To determine if LTP is enhanced in mice expressing FAD mutant presenilin-1.

脊椎动物突触可塑性的一个有希望的和广泛研究的例子 是长时程增强（LTP）， 在短暂的突触前和突触后同步 活动 有人认为，细胞和分子 负责LTP的机制将阐明生理和 病理现象，包括学习、记忆、发育突触 特异性、疼痛、神经元死亡、癫痫和痴呆。 蜂窝 已经广泛地研究了负责产生LTP的信号传导。 先前的研究表明，钙/钙调素依赖蛋白 激酶II（CaMKII）是产生LTP所必需的，也是足够的， 因此可以介导记忆的形成。 在这里，我们将研究细胞和分子的后果增加 CaMKII活性可能有助于LTP。 核心假设是 增加的突触后CaMKII活性增加了 兴奋性突触处AMPA受体的数量： 含有和不含有AMPA受体。 这将被检查 通过包括电生理学在内的几种补充方法， GFP标记受体的双光子成像和免疫组织化学 用光学和电子显微镜。 这些研究将使用啮齿动物 海马切片（急性和器官型）和分离培养 神经元 理解细胞信号传导的主要动机 是为了理解和减轻疾病 影响这些功能。 为了实现这一目标，我们将研究LTP， CaMK Ⅱ在表达突变PS-1蛋白转基因小鼠中的作用 与老年痴呆症密切相关 这种蛋白质干扰钙 我们的初步数据显示，这些小鼠具有异常的 大型LTP SA 1：为了确定CaMK II增加突触的机制， AMPA受体功能。 SA 2：确定CaMKII是否将沉默突触转化为功能性突触 突触 SA 3：确定树突状细胞胞吐是否在LTP中起作用。 SA 4：确定在表达FAD突变体的小鼠中LTP是否增强 早老素-1。