Role of postsynaptic synaptotagmins in synaptic plasticity

中心PI：马伦卡，罗伯特C.首席研究员(项目1)：马伦卡，罗伯特C./Südhof，托马斯 项目摘要 哺乳动物大脑经历长时间的、依赖活动的突触功能变化的能力 而结构对许多形式的适应性的神经回路修改起着重要作用 以及病理性的经验依赖性可塑性，包括学习和记忆。这类产品的领先模式 突触可塑性是NMDA受体依赖的长时程增强(LTP)。尽管已经取得了进展 在理解LTP潜在的机制方面，仍有许多未知之处。该项目将执行 首次检验突触后突触集束(Syts)的新假说的实验 在长时程增强过程中AMPA受体向质膜的运输以及在细胞生长过程中起关键作用 伴随着LTP的树枝状刺。已知系统可触发突触前神经递质的释放 但其潜在的突触后功能在很大程度上是未知的。这些实验将使用 一种“分子置换”策略，包括同时敲除或基因缺失 在单个海马区锥体细胞中表达野生型或突变型SYT“替换”版本的系统 体内或体外。急性海马脑片电生理检测和细胞生物学检测 将进行神经元培养，以确定SYT操作对基础突触的影响 反应、长时程增强、长期抑郁和AMPA受体胞吐和内吞。的作用 LTP伴随的脊椎生长的突触后系统也将被检查。初步证据 支持LTP中专门用于突触后Syt1和7的角色。我们将集中在分子操作上 这些蛋白质是条件基因敲除小鼠已经可以获得的。这些实验将阐明 哺乳动物大脑中兴奋性突触可能被修饰的新的分子机制 各种形式的依赖经验的可塑性，包括学习和记忆。结果也将揭晓 突触可塑性背后的突触后膜运输的新的创新研究领域。在……里面 此外，这项研究将提供对开发修改突触的药物至关重要的信息 以促进认知功能和缓解精神症状的方式传播。 相关性 学习和记忆涉及到神经细胞之间的通讯的长期改变 物理连接，这被称为突触。这个项目将使用复杂的实验技术 以阐明这种修饰发生的一些关键分子机制。这些信息 将收集到的信息对于开发更有效的认知恶化治疗方法是必不可少的 伴随着多种形式的精神疾病的功能。

Center PI: Malenka, Robert C. Principal Investigator (Project 1): Malenka, Robert C./Südhof, Thomas Project Summary The ability of the mammalian brain to undergo long-lasting, activity-dependent changes in synaptic function and structure importantly contributes to the neural circuit modifications that underlie many forms of adaptive and pathological experience-dependent plasticity, including learning and memory. A leading model for such synaptic plasticity is NMDA receptor-dependent long-term potentiation (LTP). Although progress has been made in understanding the mechanisms underlying LTP, much remains unknown. This project will perform experiments that for the first time examine the novel hypothesis that postsynaptic synaptotagmins (Syts) are critical for the trafficking of AMPA receptors to the plasma membrane during LTP and also in the growth of dendritic spines that accompanies LTP. Syts are known to trigger the presynaptic release of neurotransmitter in response to calcium but their potential postsynaptic functions are largely unknown. The experiments will use a “molecular replacement” strategy, which incorporates the simultaneous knockdown or genetic deletion of Syts with expression of a “replacement” version of wildtype or mutant Syt in single hippocampal pyramidal cells in vivo or in vitro. Electrophysiological assays in acute hippocampal slices and cell biological assays in cultured neurons will be performed to determine the consequences of Syt manipulations on basal synaptic responses, LTP, long-term depression and AMPA receptor exocytosis and endocytosis. The role of postsynaptic Syts on the spine growth that accompanies LTP will also be examined. Preliminary evidence supports a role specifically for postsynaptic Syt1 and 7 in LTP. We will focus on molecular manipulations of these proteins for which conditional knockout mice are already available. These experiments will elucidate novel molecular mechanisms by which excitatory synapses in the mammalian brain are likely modified during various forms of experience-dependent plasticity, including learning and memory. The results will also open up new, innovative areas of research on the postsynaptic membrane trafficking underlying synaptic plasticity. In addition, this research will provide information that is critical for the development of agents that modify synaptic transmission in ways that promote cognitive function and alleviate psychiatric symptoms. Relevance Learning and memory involve long-lasting modification of the communication between nerve cells at their physical connections, which are termed synapses. This project will use sophisticated experimental techniques to elucidate some of the key molecular mechanisms underlying how this modification happens. The information that will be collected is essential for developing more effective treatments for the deterioration of cognitive function that accompanies many forms of mental illness.