Synaptic dysregulation in a mouse model of Alzheimer's disease

阿尔茨海默病小鼠模型中的突触失调

• 批准号: 7935556
• 负责人: DANIEL A NICHOLSON
• 金额: $ 24.9万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7935556
• 关键词: Alzheimer' s Disease; Synapses; mouse model

Only recently has it become evident that distal excitatory synapses are different from proximal excitatory synapses in the hippocampus, and that these differences confer to distal synapses the same influence on neuronal output as their more proximal counterparts. Similarly, it has been shown only recently that Diochemical processing related to Alzheimer's disease (AD) targets synapses and affects the number of AMPA receptors (AMPARs) bound to their postsynaptic membrane. The proposed research will examine the mechanisms of distance-dependent synaptic scaling and their vulnerability to AD-like biochemical processing using a multi-disciplinary analysis of synapses in a mouse model of AD (the 5XFAD transgenic line) and their nontransgenic littermate controls. The central goal of this proposal is assist the Principal Investigator establish his independence and secure a tenure-track faculty position such that he can lead a major research program aimed at understanding the interplay among synapses, behavior, and disease. The Mentored Phase of this proposal will provide the applicant with training in serial section postembedding immunogold electron microscopy and whole-cell patch-clamp physiology from two experts in their fields: Dr. Yuri Geinisman and Dr. Nelson Spruston, respectively. Such multidisciplinary training will facilitate the applicant's transition to independence by enabling him to design, perform, and interpret experiments at multiple, complementary levels of analysis. In the Mentored Phase, the applicant will determine whether synapses in distal regions of the CA1 pyramidal neuron dendrites are stronger than those in more proximal regions, and whether the AD-linked genetic mutations in 5XFAD mice disrupt this distance-dependent regulation of synaptic strength. During the Independent Phase, the applicant will combine his training in electron microscopy and whole-cell patch-clamp physiology to determine whether the number, size, and plasticity in synapses throughout the dendritic axis of CA1 pyramidal neurons are regulated within single dendrites in control mice, and whether these parameters are dysregulated as a consequence of A? overproduction in 5XFAD mice. Together, the proposed experiments will help identify the contributions of synaptic subtypes to location-independent synaptic communication in hippocampal neurons, while simultaneously determining whether synapses are targeted by AD, and whether some synaptic subtypes are more at risk than others. This proposal takes advantage of the collaborative environment at Northwestern University and includes training at various light and electron microscopy workshops, laboratory-based training in cellular physiology, journal clubs, mouse genotyping, and computer programming. In addition, the training environment will provide numerous opportunities for career development through national research presentations, collaborations, mentoring students, and training on the responsible conduct of research.

直到最近，远端兴奋性突触才与海马中的近端兴奋性突触不同，并且这些差异赋予远端突触对神经元输出的影响与它们更近端的对应物相同。同样，只有最近才表明，与阿尔茨海默氏病（AD）靶向突触有关的二元化学加工，并影响与其突触后膜结合的AMPA受体（AMPARS）的数量。拟议的研究将检查依赖距离的突触缩放的机制及其易于使用AD小鼠模型（5XFAD转基因线）中突触中的多学科分析及其非转基因窝窝对照组中的突触中的多学科分析。该提案的核心目标是协助首席研究人员建立他的独立性并确保终身教师职位，以便他可以领导一项旨在理解突触，行为和疾病之间相互作用的主要研究计划。该提案的指导阶段将为申请人提供串行部分的培训后，以培训后，分配给他们的领域的两位专家：Yuri Geinisman博士和Nelson Spruston博士，分别来自两位专家。这样的多学科培训将通过使申请人能够在多个互补分析水平的多个互补水平上设计，执行和解释实验来促进申请人向独立的过渡。在指导阶段，申请人将确定CA1锥体神经元树突的远端区域中的突触是否比更近端区域的突触更强，以及5XFAD小鼠中AD连接的基因突变是否破坏了这种距离依赖于这种突触强度的距离依赖性调节。在独立阶段，申请人将结合他在电子显微镜和全细胞斑块夹生理学上的训练，以确定在CA1锥体神经元的整个树突状轴上是否在对照小鼠中调节了整个CA1锥体神经元的突触中的数量，大小和可塑性，以及这些参数是否均在A A A A A ADNEDEREN中。 5xFAD小鼠的过量生产。共同提出的实验将有助于确定突触亚型对海马神经元中与位置无关的突触通信的贡献，同时确定AD的突触是否是AD靶向的，以及某些突触子类型是否比其他突触更大。该建议利用西北大学的协作环境，包括各种光和电子显微镜研讨会的培训，基于实验室的蜂窝生理学培训，期刊俱乐部，鼠标基因分型和计算机编程。此外，培训环境将通过国家研究演讲，合作，指导学生以及负责任的研究进行培训来为职业发展提供许多机会。