Connecting mGluR and cAMP in the pre-clinical model of Fragile X

描述(申请人提供)：脆性X综合征(FXS)是一种常见的精神障碍形式，其原因是Fmr1基因发生突变，导致FMRP(脆性X智力低下蛋白)缺乏表达。在理解FXS方面取得了巨大的进步，这是通过使用动物模型进行的临床前研究取得的。Fmr1基因敲除小鼠模型复制了与FXS相关的表型的许多方面，包括认知缺陷、多动、多觉醒和社交能力受损。与FXS相关的一个主要病理生理学机制是增强型代谢型谷氨酸受体(MGluR)介导的突触长期抑制(mGluR-LTD)，提示mGluR信号的过度激活可能在FXS的发病机制中发挥作用。因此，有必要确定mGluR信号级联中的关键分子成分，并开发治疗策略。在这里，我们发现，降低基础cAMP水平会导致与FXS相反的突触表型。然而，cAMP是否是mGluR信号级联中的一个功能成分尚不清楚。同样重要的是，确定具体的方法来操纵FXS中的基础cAMP水平并实现治疗。与NIH的使命一致，该提案旨在确定mGluR信号级联中的新成分，并验证在小鼠动物模型中治疗FXS的新治疗策略。该方案的目的是1)确定mGluR和cAMP是如何偶联的，2)确定如何在FXS小鼠模型中操作基础和mGluR刺激的cAMP水平，以及3)确定cAMP操作在FXS中的治疗价值。我们将使用遗传方法来操纵营地的水平。我们将通过测量mGluR-LTD，与FXS相关的核心行为表型，以及FXS病理基础的关键分子和细胞机制，进一步检验其治疗价值。我们期待这项工作将发现新的机制，并提出新的治疗FXS的策略。我们操作cAMP的方法及其在FXS中的治疗价值将在使用FXS动物模型的临床前研究中得到验证。由于Fmr1基因突变也是导致自闭症的主要原因，有人认为FXS和自闭症可能有一些共同的机制。因此，我们期望这项提议的结果也有助于理解自闭症所涉及的信号转导。

DESCRIPTION (provided by applicant): Fragile X syndrome (FXS) is a common form of mental disorder caused by genetic mutation in Fmr1 gene that leads to lack of expression of FMRP (fragile X mental retardation protein). Tremendous advances in understanding FXS are made from pre-clinical studies using animal models. The Fmr1 knockout mouse model replicates many aspects of phenotypes associated with FXS, including cognition deficits, hyperactivity, hyperarousal, and impaired social ability. One major pathophysiology associated with FXS, the enhanced group I metabotropic glutamate receptor (mGluR)-mediated synaptic long-term depression (mGluR-LTD), implicates that overactivation of mGluR signaling may play a role in FXS etiology. Thus, there is significant need to identify key molecular components in the mGluR signaling cascade and develop therapeutic strategies. Here, we found that lowering basal cAMP level caused an opposite synaptic phenotype to that of FXS. However, it is not known whether cAMP is a functional component in the mGluR signaling cascade. It is also important to identify specific approaches to manipulate basal cAMP level in FXS and achieve therapy. Consistent with the mission of NIH, this proposal aims to identify a novel component in the mGluR signaling cascade and validate a new therapeutic strategy for the treatment of FXS in mouse animal model. The goals of this proposal are 1) to determine how mGluR and cAMP are coupled, 2) to determine how to manipulate the basal, as well as mGluR-stimulated cAMP level in the mouse model of FXS, and 3) to determine the therapeutic value of cAMP manipulation in FXS. We will use genetic approaches to manipulate the cAMP level. We will further examine the therapeutic value by measuring mGluR-LTD, the core FXS-associated behavioral phenotypes, and the key molecular and cellular mechanisms underlying the pathology of FXS. We expect that this work will identify novel mechanism and suggest new strategy to treat FXS. Our method of manipulating cAMP and its therapeutic value in FXS will be validated in pre-clinical studies using an FXS animal model. Because mutation of Fmr1 gene is also a leading cause for autism, it has been suggested that FXS and autism may share some common mechanisms. Thus, we expect that the outcome of this proposal may also help understanding the signal transduction involved in autism.