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

 描述（由申请人提供）：越来越多的证据表明，在阿尔茨海默病和其他痴呆疾病中，突触功能严重受损，甚至在这些疾病的早期阶段导致认知缺陷。蛋白磷酸酶-1（PP 1）在突触认知功能中起着重要作用。PP 1被称为健忘分子。尽管PP 1在突触可塑性和认知中至关重要，但PP 1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，抑制剂-2（inhibitor-2，I-2）是海马和皮层中一种重要的内源性PP 1结合蛋白，调节PP 1的活性和功能，参与突触可塑性和记忆。具体地说，我们发现，I-2是必要的诱导NMDA受体依赖的LTD，并在基础突触传递以及执行重要的功能。此外，我们发现，I-2抑制记忆形成的基础上，我们的研究在小鼠模型中，其中一个拷贝的I-2基因被删除，并在研究中的大鼠注射慢病毒敲低I-2在大鼠大脑中。有趣的是，我们的生化和行为研究表明，I-2主要作为一个积极的PP 1调节器，尽管它的名字，在调节神经元的通信和记忆的形成。 在这个建议中，我们提出了三个目标，以确定I-2的机制，在调节PP 1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）。我们将使用分子置换研究来确定I-2在正调节PP 1活性（Aim 1）、突触传递（Aim 2）和记忆形成（Aim 3）中的结构基础。 我们提出的工作将确定I-2积极调节神经元中PP 1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， 记忆功能。这些信息将有助于阐明突触功能，记忆和认知领域，也将为治疗痴呆症的治疗干预提供新的靶点。

 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.