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）是一种常见的精神疾病，由Fmr 1基因突变导致FMRP（脆性X智力低下蛋白）表达缺失引起。通过使用动物模型的临床前研究，在理解FXS方面取得了巨大进展。Fmr 1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、过度觉醒和社交能力受损。与FXS相关的一个主要病理生理学，即增强的I组代谢型谷氨酸受体（mGluR）介导的突触长时程抑制（mGluR-LTD），暗示mGluR信号传导的过度激活可能在FXS病因学中起作用。因此，有显着的需要，以确定在mGluR信号级联的关键分子组成部分，并开发治疗策略。 在这里，我们发现，降低基础cAMP水平导致相反的突触表型的FXS。然而，尚不清楚cAMP是否是mGluR信号级联中的功能组分。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，该提案旨在鉴定mGluR信号级联中的新组分，并验证用于治疗小鼠动物模型中FXS的新治疗策略。该提议的目标是1）确定mGluR和cAMP如何偶联，2）确定如何操纵FXS小鼠模型中的基础以及mGluR刺激的cAMP水平，以及3）确定cAMP操纵在FXS中的治疗价值。我们将使用遗传方法来操纵cAMP水平。我们将通过测量mGluR-LTD、核心FXS相关行为表型以及FXS病理学基础的关键分子和细胞机制来进一步研究治疗价值。我们希望这项工作将确定新的机制，并提出新的策略来治疗FXS。我们操纵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Fmr 1基因突变也是导致自闭症的主要原因，因此有人认为FXS和自闭症可能有一些共同的机制。因此，我们希望这项提议的结果也有助于理解自闭症中涉及的信号转导。

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.