Inhibitor-2 is a positive regulator for PP1's synaptic and cognitive functions

Inhibitor-2 是 PP1 突触和认知功能的正调节因子

• 批准号: 9415152
• 负责人: HOUHUI XIA
• 金额: $ 38.45万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9415152
• 关键词: AMPA Receptors; Alzheimer' s Disease; Behavior; Binding Proteins; Biochemical; Brain region; CREB1 gene; Cell Nucleus; Cognition; Cognitive deficits; Communication; Data; Degenerative Disorder; Dementia; Disease; Embryo; Frequencies; Gene Expression; Genes; Genetic study; Goals; Hippocampus (Brain); Homologous Gene; In Vitro; Injectable; Knockout Mice; Knowledge; Laboratories; Long-Term Depression; Long-Term Potentiation; Mediating; Memory; Molecular; Mus; N-Methyl-D-Aspartate Receptors; Names; Neurodegenerative Disorders; Neurons; Nuclear; Patients; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Protein phosphatase; Proteins; Rattus; Regulation; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Slice; Slide; Structure; Subfamily lentivirinae; Surface; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Therapeutic; Therapeutic Intervention; Work; base; behavioral study; cognitive function; density; genetic regulatory protein; in vivo; inhibitor/antagonist; insight; knock-down; mouse model; mutant; new therapeutic target; novel; prevent; protein phosphatase inhibitor-1; public health relevance; small hairpin RNA; synaptic function; yeast genetics

 DESCRIPTION (provided by applicant): Mounting evidence suggests that synaptic function is severely compromised in Alzheimer's disease and other dementia diseases, leading to cognitive defects even during the early stages of these diseases. It is well known that protein phosphatase-1 (PP1) plays a critical role in synaptic cognitive functions. PP1 is dubbed a molecule of forgetfulness. Despite the critical importance of PP1 in synaptic plasticity and cognition, how PP1 activity might be controlled in cognition has remained unclear. Our preliminary studies suggest that inhibitor-2 (I-2) is a critical endogenous PP1 binding protein in hippocampus and cortex, regulating PP1 activity and function in synaptic plasticity and memory. Specifically, we found that I-2 is necessary for the induction of NMDA receptor dependent LTD and performs important functions in basal synaptic transmission as well. Moreover, we found that I-2 constrains memory formation based on our studies in a mouse model in which one copy of I-2 gene was deleted and in studies of rat injected with lentivirus to knockdown I-2 in rat hippocampi. Interestingly, both our biochemical and behavioral studies indicate that the I-2 mainly functions as a positive PP1 regulator, despite its name, in regulating neuronal communication and memory formation. In this proposal, we propose three aims to define I-2 mechanisms in regulating PP1 activity and CREB inactivation (Aim 1), synaptic transmission (Aim 2), and synaptic plasticity (LTP/LTD induction) and memory formation (Aim 3). We will use molecular replacement studies to determine the structural basis of I-2 in positively regulating PP1 activity (Aim 1), synaptic transmission (Aim 2) and memory formation (Aim 3). Our proposed work will define the mechanism by which I-2 positively regulates PP1 activity in neurons and the in vivo relevance of this regulation in key forms of synaptic plasticity as well as in memory functions. This information will help clarify the field of synaptic function, memory and cognition and will also provide a novel target for therapeutic intervention in in treating dementias.

 描述（由申请人提供）：越来越多的证据表明，阿尔茨海默病和其他痴呆疾病的突触功能受到严重损害，甚至在这些疾病的早期阶段也会导致认知缺陷。众所周知，蛋白磷酸酶-1 (PP1) 在突触认知功能中起着至关重要的作用。 PP1被称为健忘分子。尽管 PP1 在突触可塑性和认知中至关重要，但如何在认知中控制 PP1 活性仍不清楚。 我们的初步研究表明，inhibitor-2 (I-2) 是海马和皮质中关键的内源性 PP1 结合蛋白，调节 PP1 活性和突触可塑性和记忆功能。具体来说，我们发现 I-2 对于诱导 NMDA 受体依赖性 LTD 是必需的，并且在基础突触传递中也发挥重要功能。此外，根据我们在小鼠模型中的研究（其中一个I-2基因拷贝被删除）以及在大鼠注射慢病毒以敲低大鼠海马中的I-2的研究，我们发现I-2限制记忆形成。有趣的是，我们的生化和行为研究都表明，尽管 I-2 的名字如此，但其主要功能是作为正 PP1 调节剂，调节神经元通讯和记忆形成。 在本提案中，我们提出了三个目标来定义调节 PP1 活性和 CREB ​​失活（目标 1）、突触传递（目标 2）、突触可塑性（LTP/LTD 诱导）和记忆形成（目标 3）的 I-2 机制。我们将利用分子替代研究来确定 I-2 在正向调节 PP1 活性（目标 1）、突触传递（目标 2）和记忆形成（目标 3）方面的结构基础。 我们提出的工作将定义 I-2 积极调节神经元中 PP1 活性的机制，以及这种调节在突触可塑性关键形式中的体内相关性以及 在记忆功能中。这些信息将有助于阐明突触功能、记忆和认知领域，也将为痴呆症的治疗干预提供新的目标。