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

 描述(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症疾病的突触功能严重受损，即使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关键作用。PP1被称为健忘分子。尽管PP1在突触可塑性和认知中起着至关重要的作用，但PP1的活性如何在认知中受到控制仍不清楚。我们的初步研究表明，抑制物-2(I-2)是一种重要的内源性PP1结合蛋白，在突触可塑性和记忆中调节PP1的活性和功能。具体地说，我们发现I-2在NMDA受体依赖性LTD的诱导中是必需的，并且在基础突触传递中也发挥着重要的作用。此外，我们在I-2基因一个拷贝缺失的小鼠模型中以及在大鼠注射慢病毒敲除大鼠海马区I-2的研究中发现，I-2抑制记忆的形成。有趣的是，我们的生化和行为学研究表明，I-2尽管名为PP1，但主要作为正性PP1调节因子，调节神经元的交流和记忆形成。在这个提案中，我们提出了三个目标来定义I-2在调节PP1活性和CREB失活(目标1)、突触传递(目标2)以及突触可塑性(LTP/LTD诱导)和记忆形成(目标3)方面的机制。我们将使用分子置换研究来确定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。我们拟议的工作将定义I-2积极调节神经元PP1活性的机制，以及这种调节在突触可塑性的关键形式中的体内相关性，以及 在内存功能中。这些信息将有助于阐明突触功能、记忆和认知领域，也将为治疗痴呆的治疗干预提供一个新的靶点。

 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.