Synaptic Depression: Focus on Cdk5 Signaling

 描述(申请人提供)：先前的研究揭示了细胞周期蛋白依赖性激酶5(CDK5)在突触可塑性、行为和认知中的关键作用，但也提出了一个关于CDK5信号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，我们在培养的大鼠脑片和完整的大脑中检测了海马CA1突触中的CDK5信号。我们发现，CDK5在与其神经元特异性调节亚单位p35结合后被激活，通过一种内稳态机制抑制了信号的传递。令人惊讶的是，CDK5在15−30min内迅速抑制了信号的传递。这一结果将CDK5与所有已知的在从几个小时到几天的时间窗口中起作用的动态平衡传递调节剂(例如，Aβ和Arc)区分开来。此外，我们在完整的动物中过表达了p25，这是p35的切割产物，也是更有效的CDK5激活剂。在阿尔茨海默病患者中可以看到p25的慢性过度表达，导致突触密度降低和突触大小增加，这是阿尔茨海默病早期突触病理的标志。这一结果指定p25为第一个能够诱导这种疾病特有的突触病理的分子。总之，我们的初步数据表明，在中央突触存在一种新的快速传递稳态，并为阿尔茨海默病的早期发病机制提供了一种新的机制。基于我们的初步发现，我们建议使用海马培养切片制备(AIM 1)来研究CDK5信号如何调节中央突触的一种新的快速突触动态平衡。我们期望这项研究将确定CDK5信号的突触作用，并提出一个新的分子靶点(和策略)来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中，以检查阿尔茨海默病患者中p25的慢性过度生产是如何导致典型的早期阿尔茨海默病样突触病理和认知障碍的(目标2)。我们期待该检测将揭示阿尔茨海默病发病机制的新机制，并为其发病机制建立动物模型。最后，我们将探索可能逆转动物模型中突触病理和认知障碍的药理学和遗传操作(目标3)。我们预计，这项探索将为阿尔茨海默病开发出替代治疗方案。

 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.