Protein Kinase C Isozymes in Hippocampal Plasticity

海马可塑性中的蛋白激酶 C 同工酶

基本信息

批准号：
8011226
负责人：
TODD C SACKTOR
金额：
$ 39.4万
依托单位：
SUNY DOWNSTATE MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-01-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8011226
关键词：
1,2-diacylglycerol AMPA Receptors Affect Amnestic Disorder Behavioral Binding Binding Sites Brain C-terminal Catalytic Domain Chemosensitization Clinical Complex Cytosol Data Dendrites Dendritic Spines Diglycerides Enzymes Feedback Felis catus Functional disorder Genes Hippocampus (Brain)Hour Information Storage Injection of therapeutic agent Isoenzymes Knowledge Laboratories Learning Length Long-Term Potentiation Maintenance Mediating Membrane Memory Memory Disorders Messenger RNA Mitogen-Activated Protein Kinase Kinases Molecular Molecular Conformation N-ethylmaleimide-sensitive protein N-terminal Neurology Neurons Neurosciences Pathway interactions Phase Phosphorylation Phosphotransferases Physiological Play Protein Biosynthesis Protein Isoforms Protein Kinase Protein Kinase C Proteins Psychiatry Role Science Second Messenger Systems Short-Term Memory Signal Pathway Signal Transduction Site Synapses Synaptic Transmission Synaptic plasticity Testing Time Translations Vertebral column extracellular inhibitor/antagonist long term memory mTOR protein memory retention neuronal cell body postsynaptic promoter public health relevance receptor second messenger trafficking

项目摘要

DESCRIPTION (provided by applicant): Long-term changes in synaptic strength are widely believed to underlie memory storage. Thus one approach to understanding memory storage is to investigate long-term synaptic plasticity, particularly a persistent synaptic enhancement induced by strong afferent stimulation, long-term potentiation (LTP). The mechanisms of LTP can be divided into 2 phases: induction, triggering the potentiation, and maintenance, sustaining the potentiation over time. Although inducing persistent LTP requires new protein synthesis and involves complex signaling mechanisms, the functionally important, newly synthesized proteins maintaining LTP, and whether they play similar roles in memory storage, had previously been unknown. Recently, we found that a constitutively active PKC isoform, PKMzeta (PKM6), is both necessary and sufficient for maintaining LTP. Produced from a PKM6 mRNA, PKM6 is the independent catalytic domain of PKC6, which, lacking an autoinhibitory regulatory domain, persistently phosphorylates without second messenger stimulation. Once synthesized in LTP induction, persistent PKM6 activity maintains synaptic potentiation because inhibiting PKM6 reverses established LTP, even when the inhibition begins hours after induction. Moreover, inhibiting PKM6 disrupts behavioral long-term memory retention, even days after learning, without affecting subsequent memory storage. Thus, the overall hypothesis of this application is that persistent increases in PKM6 at synapses may be a common molecular mechanism of information storage for both LTP maintenance and behavioral long-term memory. This application therefore focuses on the physiological mechanisms for initially encoding and persistently maintaining PKM6 at synapses. Our first aim is to examine the mechanisms of PKM6 synthesis in the phases of LTP, focusing on a positive feedback loop that might increase PKM6 levels through dendritic protein synthesis. Second is to examine changes in the distribution of PKM6 in neurons during LTP. We will examine if PKM6 activity maintains its targeting to spines by its autonomous activity and through the same trafficking mechanism by which the kinase also potentiates synaptic strength. Third, we will determine if these mechanisms of synthesis and synaptic compartmentalization are the same in behavioral memory storage. Preliminary data indicate that PKM6 in the hippocampus increases after learning and correlates with the extent of memory retention. Thus our 3 aims will provide fundamental new knowledge on how PKM6 maintains activity- dependent information within neurons, which might be a common mechanism for synaptic and behavioral memory storage that may be relevant to disorders of memory. PUBLIC HEALTH RELEVANCE: How long-term memories are stored is a fundamental question in neuroscience with important clinical implications for neurology and psychiatry. Our laboratory has identified a molecular component of the storage mechanism of long-term memory, a protein kinase termed PKMzeta, by studying the maintenance mechanism of a persistent form of synaptic plasticity, long-term potentiation (LTP). This application focuses on the physiological mechanisms for initially encoding and persistently maintaining PKMzeta at synapses that might be common mechanisms for information storage during both LTP and long-term memory, and thus relevant to the pathophysiology of amnestic disorders.

描述（由申请人提供）：人们普遍认为突触强度的长期变化是记忆存储的基础。因此，理解记忆存储的一种方法是研究长期突触可塑性，特别是由强传入刺激、长期增强（LTP）诱导的持续突触增强。 LTP 的机制可分为 2 个阶段：诱导、触发增强和维持、随着时间的推移维持增强。尽管诱导持续性 LTP 需要新的蛋白质合成并涉及复杂的信号传导机制，但功能上重要的新合成的维持 LTP 的蛋白质以及它们是否在记忆存储中发挥类似的作用此前仍不清楚。最近，我们发现组成型活性 PKC 亚型 PKMzeta (PKM6) 对于维持 LTP 是必要且充分的。 PKM6 由 PKM6 mRNA 产生，是 PKC6 的独立催化结构域，缺乏自抑制调节结构域，可在没有第二信使刺激的情况下持续磷酸化。一旦在 LTP 诱导中合成，持续的 PKM6 活性就会维持突触增强，因为抑制 PKM6 会逆转已建立的 LTP，即使在诱导后数小时内开始抑制。此外，抑制 PKM6 会破坏行为长期记忆保留，甚至在学习后几天，也不影响随后的记忆存储。因此，本申请的总体假设是，突触处 PKM6 的持续增加可能是 LTP 维持和行为长期记忆的信息存储的常见分子机制。因此，本申请重点关注突触处初始编码和持久维持 PKM6 的生理机制。我们的首要目标是研究 LTP 阶段 PKM6 合成的机制，重点关注可能通过树突蛋白合成增加 PKM6 水平的正反馈循环。其次是检查 LTP 期间神经元中 PKM6 分布的变化。我们将检查 PKM6 活性是否通过其自主活性以及通过激酶也增强突触强度的相同运输机制来维持其对棘的靶向。第三，我们将确定这些合成和突触区划的机制在行为记忆存储中是否相同。初步数据表明，海马体中的 PKM6 在学习后增加，并且与记忆保留程度相关。因此，我们的 3 个目标将提供关于 PKM6 如何在神经元内维持活动依赖性信息的基本新知识，这可能是可能与记忆障碍相关的突触和行为记忆存储的常见机制。公共健康相关性：长期记忆如何存储是神经科学的一个基本问题，对神经病学和精神病学具有重要的临床意义。我们的实验室通过研究持久形式的突触可塑性、长时程增强（LTP）的维持机制，确定了长期记忆存储机制的分子成分，即一种名为 PKMzeta 的蛋白激酶。本申请重点关注突触处最初编码和持久维持 PKMzeta 的生理机制，这可能是 LTP 和长期记忆期间信息存储的常见机制，因此与遗忘症的病理生理学相关。