Role of postsynaptic synaptotagmins in synaptic plasticity

突触后突触结合蛋白在突触可塑性中的作用

• 批准号: 8854548
• 负责人: ROBERT C MALENKA
• 金额: $ 37.37万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8854548
• 关键词: AMPA Receptors; Acute; Affinity; Alanine; Area; Aspartate; Binding; Biochemical; Biological Assay; Brain; Brain Diseases; Calcium; Cell membrane; Cells; Communication; Complex; Dendritic Spines; Dependence; Deterioration; Development; Endocytosis; Epitopes; Excitatory Synapse; Exocytosis; Frequencies; Genetic; Growth; Hippocampus (Brain); Image; Imagery; In Vitro; Kinetics; Knock-out; Knockout Mice; Learning; Location; Long-Term Depression; Long-Term Potentiation; Mediating; Membrane Protein Traffic; Memory; Mental disorders; Modeling; Modification; Molecular; Mutate; N-Methyl-D-Aspartate Receptors; Neurons; Peptide Hydrolases; Phosphorylation; Physiologic pulse; Play; Postsynaptic Membrane; Preparation; Principal Investigator; Proteins; Protocols documentation; Pyramidal Cells; Recombinants; Research; Resistance; Role; S-nitro-N-acetylpenicillamine; SNAP receptor; Site; Slice; Structure; Surface; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Testing; Time; VAMP-2; Vertebral column; Vesicle; Work; cognitive function; effective therapy; experience; in vivo; innovation; mutant; neural circuit; neurotransmitter release; novel; postsynaptic; presynaptic; prevent; recombinase; research study; response; small hairpin RNA; synaptic function; synaptotagmin; syntaxin 3; trafficking; voltage

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.

中心PI：Malenka，Robert C.主要研究者（项目1）：Malenka，Robert C./ Südhof，托马斯 项目摘要 哺乳动物大脑在突触功能上经历持久的、活动依赖性变化的能力 和结构重要地有助于神经回路的修改，这些修改是许多形式的自适应的基础。 和病理经验依赖性可塑性，包括学习和记忆。一个领先的模型， 突触可塑性是NMDA受体依赖性长时程增强（LTP）。尽管进展 在理解LTP的机制方面取得了很大进展，但仍有许多未知之处。该项目将执行 实验首次检验了新的假设，即突触后突触结合蛋白（Syts）是 在LTP过程中，AMPA受体向质膜的运输以及细胞生长中， 伴随LTP的树突棘突触后兴奋性突触后兴奋性突触前兴奋性突触后兴奋性突触前兴奋性突触后兴奋性突触后 但其潜在的突触后功能在很大程度上是未知的。实验将使用 一种“分子替代”策略，它包括同时敲低或基因缺失， 在单个海马锥体细胞中表达野生型或突变型Syt的“替代”版本的Syt 在体内或体外。急性海马脑片的电生理学测定和急性脑缺血的细胞生物学测定。 将进行培养的神经元以确定Syt操作对基底突触的影响。 反应，LTP，长期抑郁症和AMPA受体胞吐和胞吞。的作用 还将检查突触后Syts对伴随LTP的脊柱生长的影响。初步证据 支持突触后Syt 1和7在LTP中的特定作用。我们将集中在分子操纵的 条件性基因敲除小鼠已经可以获得这些蛋白质。这些实验将阐明 新的分子机制，哺乳动物大脑中的兴奋性突触可能会被修改， 各种形式的经验依赖性可塑性，包括学习和记忆。结果也将打开 新的，创新的研究领域的突触后膜运输突触可塑性的基础。在 此外，这项研究将提供信息，这是关键的药物的发展，修改突触 传播的方式，促进认知功能和减轻精神症状。 相关性 学习和记忆涉及神经细胞之间的通信的长期修改， 物理连接，这被称为突触。这个项目将使用先进的实验技术 来阐明这种修饰如何发生的一些关键分子机制。的信息 对于开发更有效的治疗认知功能恶化的方法至关重要。 伴随许多形式的精神疾病的功能。