Synaptic Depression: Focus on Cdk5 Signaling

突触抑制：关注 Cdk5 信号传导

• 批准号: 9513061
• 负责人: J. Julius Zhu
• 金额: $ 34.29万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-20 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9513061
• 关键词: Address; Alzheimer like pathology; Alzheimer' s Disease; Amyloid beta-Protein; Animal Model; Animals; Behavior; Brain; Characteristics; Chronic; Cognition; Cyclin-Dependent Kinase 5; Cytoskeleton; Data; Depressed mood; Disease; Exhibits; Genetic; Hippocampus (Brain); Homeostasis; Homosynaptic Depression; Hour; Impaired cognition; Impairment; Investigation; Lead; Learning; Long-Term Depression; MAPK14 gene; MAPK8 gene; Mediating; Memory; Mental Depression; Neurons; Pathogenesis; Pathologic; Pathology; Patients; Pharmacology; Phosphotransferases; Physiological; Pilot Projects; Preparation; Production; Property; Protein-Serine-Threonine Kinases; Proteins; Rattus; Regulation; Role; Signal Transduction; Slice; Status Epilepticus; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Therapeutic; Therapeutic Intervention; Time; Transgenic Mice; Yang; base; density; design; experimental study; genetic manipulation; inhibitor/antagonist; mitogen-activated protein kinase p38; novel; overexpression; prevent; public health relevance; response; small hairpin RNA; small molecule inhibitor; synaptic depression; synaptic function; transmission process

 DESCRIPTION (provided by applicant): The previous investigation has revealed a pivotal role for cyclin-dependent kinase 5 (Cdk5) in synaptic plasticity, behavior and cognition, but also raised a fundamental question on how Cdk5 signaling regulates synaptic plasticity and behavior. To address this question, we examined Cdk5 signaling at hippocampal CA1 synapses in rat cultured slices and intact brains. We found that Cdk5, which is activated upon association with its neuron-specific regulatory subunit p35, depressed transmission using a homeostatic mechanism. Surprisingly, Cdk5 depressed transmission rapidly within 15−30 min. This result distinguishes Cdk5 from all known homeostatic transmission regulators (e.g., Aβ and Arc) that act in the time windows from hours to days. Moreover, we overexpressed p25, a cleavage product of p35 and more potent activator of Cdk5, in intact animals. Chronic overproduction of p25, seen in Alzheimer's patients, induced the concurrent reduction in synapse density and increase in synaptic size, the hallmark early synaptic pathology of Alzheimer's disease. This result designates p25 as the first molecule capable of inducing the characteristic synaptic pathology of the disease. Together, our preliminary data suggest a novel rapid transmission homeostasis at central synapses and a new mechanism for the early pathogenesis of Alzheimer's disease. Based on our preliminary findings, we propose to investigate how Cdk5 signaling regulates a novel rapid synaptic homeostasis at central synapses using a hippocampal cultured slice preparation (Aim 1). We expect that the investigation will define the synaptic role of Cdk5 signaling, and suggest a new molecule target (and strategy) for preventing the rapid status epilepticus. We also plan to extend the study into intact animals to examine how chronic overproduction of p25, seen in Alzheimer's patients, induces the characteristic early Alzheimer-like synaptic pathology and cognitive impairments (Aim 2). We expect that the examination will reveal a new mechanism for the pathogenesis of Alzheimer's disease, and establish an animal model for the pathogenesis. Finally, we will explore pharmacological and genetic manipulations that may reverse the synaptic pathology and cognitive impairments in the animal model (Aim 3). We expect that the exploration will develop alternative therapeutic options for Alzheimer's disease.

 描述（申请人提供）：之前的研究揭示了细胞周期蛋白依赖性激酶5（Cdk 5）在突触可塑性、行为和认知中的关键作用，但也提出了关于Cdk 5信号传导如何调节突触可塑性和行为的基本问题。为了解决这个问题，我们研究了Cdk 5信号在海马CA 1突触在大鼠培养切片和完整的大脑。我们发现，Cdk 5，这是激活后，与其神经元特异性调节亚基p35，抑郁症的传输使用一个稳态机制。令人惊讶的是，Cdk 5在15 - 30分钟内迅速抑制了传输。这一结果将Cdk 5与所有已知的稳态传输调节因子（例如，Aβ和Arc），其在从数小时到数天的时间窗口中起作用。此外，我们过表达p25，p35的切割产物和更有效的Cdk 5激活剂，在完整的动物。在阿尔茨海默病患者中观察到的p25的慢性过度产生诱导突触密度的同时减少和突触大小的增加，这是阿尔茨海默病早期突触病理学的标志。这一结果表明p25是第一个能够诱导该疾病特征性突触病理的分子。总之，我们的初步数据表明，一种新的快速传输稳态在中央突触和阿尔茨海默病的早期发病机制的新机制。 基于我们的初步研究结果，我们建议使用海马培养切片制备物（Aim 1）研究Cdk 5信号传导如何调节中枢突触的新型快速突触稳态。我们希望这项研究将确定Cdk 5信号传导的突触作用，并提出一个新的分子靶点（和策略），用于预防快速癫痫持续状态。我们还计划将这项研究扩展到完整的动物，以研究在阿尔茨海默病患者中观察到的p25的慢性过度产生如何诱导特征性的早期阿尔茨海默病样突触病理学和认知障碍（Aim 2）。本研究有望揭示阿尔茨海默病发病的新机制，建立阿尔茨海默病发病的动物模型。最后，我们将探索药理学和遗传操作，可能会扭转突触病理和认知障碍的动物模型（目的3）。我们希望这项探索将为阿尔茨海默病开发替代治疗方案。