CRCNS: PKMzeta-Dependent Protein Synthesis Maintains Synaptic Plasticity

CRCNS：PKMzeta 依赖性蛋白质合成维持突触可塑性

• 批准号: 9059060
• 负责人: HAREL Zeev SHOUVAL
• 金额: $ 28.46万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9059060
• 关键词: Accounting; Address; Age; Back; Behavioral; Binding; Biochemical; Biological Sciences; Biology; Brain; Calcium; Calmodulin; Chemosensitization; Clinical; Collaborations; Communities; Computational Biology; Computer Simulation; Dependence; Diffuse; Diffusion; Disadvantaged; Drug abuse; Feedback; Goals; Grant; High School Student; Hippocampus (Brain); Hour; Housing; Human; In Vitro; Information Storage; Instruction; Kinetics; Knowledge; Learning; Life; Long-Term Potentiation; Maintenance; Mediating; Memory; Mental disorders; Mentors; Methodology; Modeling; Molecular; Molecular Conformation; Neurosciences; New York; Pathway interactions; Pharmaceutical Preparations; Phase; Phosphorylation; Phosphotransferases; Play; Post-Traumatic Stress Disorders; Property; Protein Biosynthesis; Protein Isoforms; Protein Kinase; Protein Kinase C; Protein Synthesis Inhibitors; Proteins; Qualifying; Recording of previous events; Regulation; Rice; Role; Science; Scientist; Site; Slice; Solid; Students; Synapses; Synaptic Transmission; Synaptic plasticity; System; Techniques; Testing; Theoretical model; Time; Toxic effect; Training; Translations; Work; Youth; abstracting; addiction; base; biophysical model; drug reward; drug seeking behavior; education research; experience; field study; in vivo; inhibitor/antagonist; interest; link protein; long term memory; mathematical model; nervous system disorder; neuronal circuitry; novel; outreach; painful neuropathy; programs; protein degradation; research study; response; simulation; theories

DESCRIPTION (provided by applicant): We all have memories that date back to our youth; we remember the house we lived in at age 4; we remember a favorite schoolteacher. The mechanism for storing these memories is believed to be the long-term plasticity of synaptic connections within specific neuronal circuits. However, this putative cellular basis of memory relies on proteins that typically have lifetimes far shorter than the memory. Here exactly lies a fundamental problem of long-term memory and synaptic plasticity: How can memories be stored for a human lifetime on the basis of proteins that are continuously degrading? Recently, it was shown that the brain-specific PKC isoform, protein kinase Mζ(PKMζ), plays a unique role in maintaining both late long-term potentiation (L-LTP) of synapses and long-term memory. This crucial observation, however, does not explain how PKMζcan overcome the natural degrading effect of protein turnover and diffusion. The central hypothesis of this proposal is that PKMζ, through its control of its own synthesis, can form a bi-stable system, which can account for the maintenance of synapse specific long-term plasticity and memory. Here we propose to mathematically formulate this hypothesis within a biophysical model, and to analyze this model so as to propose testable experimental predictions. We then will directly test these predictions on PKMζ-mediated persistent synaptic potentiation, using novel techniques tailored for testing the theory. Intellectual Merit: The finding that PKMζ is both necessary and sufficient for the maintenance of synaptic plasticity and long-term memory has fundamentally changed the field of learning and memory, but much needs to be learned about the mechanisms that can actually accomplish the persistence of long-term plasticity and memory. This proposal addresses these questions using a combined theoretical and experimental approach. Such a theory in which bi-stability depends on regulation of translation is novel not only for neuroscience but also for biology in general. Our collaboration is uniquely qualified to carry out the proposed work because the Shouval lab has ample experience in modeling synaptic plasticity in collaboration with experimental groups, and the Sacktor lab has pioneered the science of PKM??and has ample experience with the proposed techniques. The experimental techniques include two new methodologies necessary for testing the predictions. First, we propose to test the model's predictions on protein translation in L-LTP, not by general protein synthesis inhibitors that may have issues of toxicity and indirect effects, but by use of antisense oligodeoxynucleotides directed to the translation start site of PKMζmRNA to specifically block PKMζ synthesis in induction and maintenance. Second, because PKMζ-mediated potentiation is both highly stable and yet rapidly reversible, we will use a fast-flow hippocampal slice chamber optimized for the study of the maintenance of L-LTP to test key predictions of the model. The proposed stochastic simulations of translation-dependent bi-stability are also novel in computational biology. Broader Impact: As the first demonstrated molecular mechanism of experience-dependent, long-term information storage in the brain, PKMζ has significant clinical implications, and within the last year has been shown to contribute to in the biology of a variety of neurological and psychiatric diseases, including post-traumatic stress disorder, central neuropathic pain, and drug abuse. In order to assist the rapidly growing interest in PKMζ in many labs, we will make our model accessible to the larger community, allowing for other scientists to test, modify, and incorporate their findings into the model, thus accelerating the pace of scientific discovery. Because an important goal for NSF is to integrate research and education, we will train a diverse pool of students. Our labs already train undergraduates, the Shouval lab takes undergraduates each summer through an REU program (PI S. Cox, Rice), and a UT system grant (PI H. Shouval), and local undergraduates throughout the year, and the Sacktor lab has had a long history of mentoring local disadvantaged high school students (e.g., through the Intel program). Both labs are dedicated to public outreach; for example, an article on PKMζ and memory was on the front page of The New York Times. We are eager to extend this type of outreach to the domain of the interaction between theory and experiment in biological sciences.

描述（由适用提供）：我们都有回忆的记忆，可以追溯到我们的年轻人；我们记得我们4岁时住的房子；我们记得最喜欢的学校老师。据信，存储这些记忆的机制被认为是特定神经元电路内突触连接的长期可塑性。但是，这种假定的记忆基础依赖于通常比记忆短得多的蛋白质。这是长期记忆和突触可塑性的基本问题：如何根据不断降低的蛋白质来存储记忆？最近，结果表明，脑特异性PKC同工型蛋白激酶Mζ（PKMζ）在维持突触的晚期长期潜力（L-LTP）和长期记忆方面起着独特的作用。但是，这种关键观察并不能解释PKMζ如何克服蛋白质更新和扩散的自然降解作用。该提案的中心假设是，通过控制其自身合成的PKMζ可以形成双稳定系统，该系统可以说明突触特定的长期可塑性和记忆力。在这里，我们建议在数学上在生物物理模型中提出这一假设，并分析该模型，以提出可测试的实验预测。然后，我们将使用用于测试该理论的新技术直接测试PKMζ介导的持续突触势的这些预测。知识分子的优点：发现PKMζ对于维持突触可塑性和长期记忆是必要且足够的发现，从根本上改变了学习和记忆的领域，但是关于实际上可以实现长期可塑性和记忆力持久性的机制，需要学习很多东西。该建议使用合并的理论和实验方法来解决这些问题。这种理论依赖于翻译的调节的理论不仅对神经科学，而且对生物学而言都是新颖的。我们的合作具有独特的资格来进行拟议的工作，因为Shouval实验室在与实验组合作进行突触可塑性建模方面具有丰富的经验，而Sacktor Lab则开创了PKM的科学？实验技术包括测试预测所需的两种新方法。首先，我们建议测试该模型对L-LTP中蛋白质翻译的预测，而不是通过可能具有毒性和间接作用问题的一般蛋白质合成抑制剂，而是通过使用反义寡脱氧核苷酸的毒性和间接作用的问题，该抑制剂用于PKMζMRNA的翻译起始位点，以特定阻断PKM pkm球综合和维持。其次，由于PKMζ介导的增强既既高稳定又迅速可逆，因此我们将使用优化的快速流量海马切片室来研究L-LTP的维护来测试模型的关键预测。在计算生物学中，提出的转化依赖性双稳定性的随机模拟也是新颖的。更广泛的影响：正如第一个证明了经验依赖性的分子机制，大脑中的长期信息存储，PKMζ具有重要的临床意义，并且在去年内已显示出对各种神经系统和精神疾病的生物学作用，包括多种神经系统疾病，包括创伤后应激障碍，中枢神经病患者疼痛和药物滥用。为了协助许多实验室中对PKMζ的迅速兴趣，我们将使我们的模型可以访问较大的社区，从而使其他科学家可以测试，修改并将其发现纳入模型中，从而加快了科学发现的速度。因为NSF的重要目标是整合研究和教育，所以我们将培训潜水员的学生。我们的实验室已经训练本科生，舒瓦尔实验室每年夏天通过REU计划（PI S. Cox，Rice）和UT系统赠款（Pi H. Shouval）（Pi H. Shouval）和当地的本科生，全年都有本科生的本科生，而Sacktor实验室全年都有悠久的心理灾难的高中生（例如，通过Intel Eltel Programs）具有悠久的历史。这两个实验室都致力于公共宣传。例如，《纽约时报》的首页上有关PKMζ和记忆的文章。我们渴望将这种类型的外展扩展到生物科学中理论与实验之间相互作用的领域。