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

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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. PUBLIC HEALTH RELEVANCE: Mutation in Fmr1 gene is linked to Fragile X syndrome (FXS), and also a leading cause for autism. The long-term goal of our research is to develop molecular therapies for FXS and autism. This proposal aims to identify a novel signaling pathway, and develop a new therapeutic strategy in the pre-clinical model of FXS.