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.

直到最近才变得明显，海马体中的远端兴奋性突触与近端兴奋性突触不同，并且这些差异赋予远端突触与近端突触相同的对神经元输出的影响。同样，最近才发现与阿尔茨海默病 (AD) 相关的生物化学过程以突触为目标，并影响与其突触后膜结合的 AMPA 受体 (AMPAR) 的数量。拟议的研究将通过对 AD 小鼠模型（5XFAD 转基因系）及其非转基因同窝对照中的突触进行多学科分析，研究距离依赖性突触缩放的机制及其对 AD 样生化处理的脆弱性。该提案的中心目标是帮助首席研究员建立其独立性并获得终身教授职位，以便他能够领导一项旨在了解突触、行为和疾病之间相互作用的重大研究项目。该提案的指导阶段将为申请人提供由各自领域的两位专家（分别是 Yuri Geinisman 博士和 Nelson Spruston 博士）进行的连续切片包埋后免疫金电子显微镜和全细胞膜片钳生理学方面的培训。这种多学科培训将使申请人能够在多个互补的分析水平上设计、执行和解释实验，从而促进其向独立过渡。在指导阶段，申请人将确定 CA1 锥体神经元树突远端区域的突触是否比更近端区域的突触更强，以及 5XFAD 小鼠中 AD 相关的基因突变是否破坏了突触强度的这种距离依赖性调节。在独立阶段，申请人将结合他在电子显微镜和全细胞膜片钳生理学方面的训练，以确定 CA1 锥体神经元树突轴中突触的数量、大小和可塑性是否在对照小鼠的单个树突内受到调节，以及这些参数是否由于 A? 5XFAD 小鼠中的过量生产。总之，所提出的实验将有助于确定突触亚型对海马神经元位置无关的突触通讯的贡献，同时确定突触是否是 AD 的目标，以及某些突触亚型是否比其他亚型面临更大的风险。该提案利用了西北大学的协作环境，包括各种光学和电子显微镜研讨会的培训、细胞生理学、期刊俱乐部、小鼠基因分型和计算机编程的实验室培训。此外，培训环境还将通过国家研究报告、合作、指导学生以及负责任的研究行为培训，为职业发展提供大量机会。