Tau and Glutamatergic Synapses in Frontotemporal Dementia

额颞叶痴呆中的 Tau 蛋白和谷氨酸突触

• 批准号: 8593990
• 负责人: Brian A Warmus
• 金额: $ 3.21万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2017-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8593990
• 关键词: 1 year old; AMPA Receptors; Acute; Address; Aftercare; Age; Agonist; Alzheimer' s Disease; Atrophic; Behavior; Behavioral; Biochemical; Biological Assay; Biotinylation; Cells; Corpus striatum structure; Cycloserine; Data; Dementia; Disease; Disinhibition; Excitatory Postsynaptic Potentials; Excitatory Synapse; Exhibits; Figs - dietary; Foundations; Fractionation; Frequencies; Frontotemporal Dementia; Functional disorder; Future; Genes; Glutamates; Goals; Human; Individual; Laboratories; Link; Measures; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Mutation; N-Methyl-D-Aspartate Receptors; Neurobiology; Neurodegenerative Disorders; Patients; Personality; Phosphorylation; Physicians; Prevention; Probability; Receptor Signaling; Research; Research Training; Scientist; Severities; Signal Transduction; Slice; Social Change; Societies; Solid; Surface; Symptoms; Synapses; Techniques; Testing; Training; Transgenic Mice; Ventral Striatum; Withdrawal; age related; base; career; design; human old age (65+); interest; loris; mouse model; patch clamp; presynaptic; public health relevance; skills; tau Proteins; tau mutation; therapeutic development; trafficking; transmission process

DESCRIPTION (provided by applicant): This proposal is designed to determine the synaptic and molecular mechanisms underlying repetitive behavior in ventral striatum of a mouse model of frontotemporal dementia (FTD). Tau mutations cause FTD, and we have found several FTD-relevant behavioral abnormalities in a transgenic mouse expressing the V337M human tau mutation (hTauV337M mice). We found that these mice have repetitive behavior, a core feature of FTD. hTauV337M mice have decreased excitatory transmission and altered synaptic organization in ventral striatum, which is an important mediator of repetitive behaviors in FTD. Preliminary data suggests that hTauV337M mice may have impaired NMDA receptor signaling and decreased surface AMPA receptor trafficking. We hypothesize that mutant tau protein causes repetitive behavior due to synaptic dysfunction in ventral striatum, which results from impaired NMDAR signaling causing reduced surface AMPA receptor trafficking To determine if surface AMPAR trafficking is decreased in ventral striatum of hTauV337M mice, we will measure surface AMPAR levels at the synapse by biotinylation and biochemical fractionation of ventral striatum. In addition, we will determine the functionality of surface AMPARs by recording mEPSC amplitude and frequency from acute striatal slices. To determine if NMDAR signaling is impaired in hTauV337M mice we will pharmacologically isolate and compare NMDA receptor-mediated EPSCs from acute striatal slices. We will determine if increasing NMDAR signaling with a co-agonist, D-cycloserine, can increase surface AMPAR trafficking at the synapse by measuring the synaptic surface expression of AMPARs after treatment. We will determine if increasing NMDAR signaling with a D-cycloserine can correct the decreased excitatory transmission by recording from acute striatal slices after treatment. Lastly, we will determine if increasing NMDAR signaling with a co-agonist can correct repetitive behaviors by comparing untreated and treated mice. The proposed research training plan is sponsored by Dr. Erik Roberson and co-sponsored by Dr. Lori McMahon. The overall goal of the training plan is to provide the PI an enhanced repertoire of laboratory techniques, a solid foundation in hypothesis-driven approaches in neurobiology research, and other skills necessary for a successful career as a physician scientist. Currently, there have yet to be any disease-modifying treatments for FTD and other fatal neurodegenerative diseases. The results from this proposal will help identify potential treatment targets and help direct future studies on the causes, prevention, and treatment of FTD.

描述（由申请人提供）：本提案旨在确定额颞叶痴呆（FTD）小鼠模型腹侧纹状体重复行为背后的突触和分子机制。 Tau 突变导致 FTD，我们在表达 V337M 人类 tau 突变的转基因小鼠（hTauV337M 小鼠）中发现了几种与 FTD 相关的行为异常。我们发现这些小鼠具有重复行为，这是 FTD 的核心特征。 hTauV337M 小鼠的腹侧纹状体的兴奋性传递减少并改变了突触组织，这是 FTD 重复行为的重要介质。初步数据表明，hTauV337M 小鼠的 NMDA 受体信号传导可能受损，表面 AMPA 受体运输减少。我们假设突变 tau 蛋白由于腹侧纹状体突触功能障碍而导致重复行为，这是由于 NMDAR 信号传导受损导致表面 AMPA 受体运输减少为了确定 hTauV337M 小鼠腹侧纹状体中表面 AMPAR 运输是否减少，我们将测量表面 AMPAR 水平通过腹侧纹状体的生物素化和生化分级作用在突触处。此外，我们将通过记录急性纹状体切片的 mEPSC 振幅和频率来确定表面 AMPAR 的功能。为了确定 hTauV337M 小鼠中 NMDAR 信号传导是否受损，我们将从急性纹状体切片中药理学分离并比较 NMDA 受体介导的 EPSC。我们将通过测量治疗后 AMPAR 的突触表面表达来确定使用共激动剂 D-环丝氨酸增加 NMDAR 信号传导是否可以增加突触处的表面 AMPAR 运输。我们将通过治疗后急性纹状体切片的记录来确定用 D-环丝氨酸增加 NMDAR 信号传导是否可以纠正兴奋性传递的减少。最后，我们将通过比较未治疗和治疗的小鼠来确定使用共激动剂增加 NMDAR 信号传导是否可以纠正重复行为。 拟议的研究培训计划由 Erik Roberson 博士发起，并由 Lori McMahon 博士共同发起。培训计划的总体目标是为 PI 提供增强的实验室技术、神经生物学研究中假设驱动方法的坚实基础，以及作为医师科学家成功职业生涯所需的其他技能。目前，还没有任何针对 FTD 和其他致命神经退行性疾病的疾病缓解疗法。该提案的结果将有助于确定潜在的治疗目标，并有助于指导未来对 FTD 的病因、预防和治疗的研究。