Fragile X syndrome (FXS) is a monogenic pathology responsible of the main cause of inherited intellectual disability (ID) and autism. FXS affects 1/4000 men and 1/8000 women. There is no treatment yet validated. FXS is due to the absence or the loss of function of the FMRP (Fragile X Mental Retardation Protein). The Fmr1 knock-out mouse model (Fmr1-KO) recapitulates the symptoms of FXS and demonstrates that the lack of FMRP leads to alterations of synaptic plasticity underlying neuronal troubles of FXS. FMRP is an RNA binding protein whose absence causes an excessive translation of hundreds of proteins in neurons of several brain regions. This neuronal protein synthesis excess leads to the alteration of several forms of translation-dependent synaptic plasticity. Thus, FMRP appears as a key regulator of the mechanisms underlying the inter-neuronal communication. The precise molecular function of FMRP in this process is however still not fully understood. One outstanding question that remains unresolved despite extensive research efforts is how quasi-ubiquitous FMRP controls the translation of hundreds of mRNAs specifically in neurons. In this context, understand how the absence of FMRP leads to synaptic alterations remains a major goal to define the molecular basis of FXS and identify a treatment. Towards this goal, this project is based on our recent discovery that the loss of FMRP, besides leading to protein translation excess in neurons, is also leading to diacylglycerol (DAG) and phosphatidic acid (PA) lipid signaling deregulation. In neurons, FMRP is mostly associated with diacylglycerol kinase kappa (DGKk) mRNA and positively controls its translation. DGK enzymes are the master regulators of the switch between DAG- and PA- signaling pathways that control protein translation and actin filament stability, respectively, and that are proposed to orchestrate synaptic plasticity. The loss of DGKk is sufficient to reproduce FXS associated symptoms in the mouse. These data lead to a change of paradigm in the pathological mechanism of FXS and the function of FMRP: DGKk is a primary target of FMRP in neurons and the excess of DAG and a lack of PA signaling consecutive to DGKk deregulation contributes predominantly to the pathology. These data open new avenues of research towards understanding of FMRP function, and suggests novel therapeutic means. The scientific program, based on our newly identified pathomechanism, aims at understanding the molecular basis of Fragile X syndrome by following two main axes: understand the molecular function of the FMRP protein and identify a novel way of intervention. The program is organized to achieve four distinct goals: 1) define the molecular mechanism of FMRP translation control of Dgkk in neurons, 2) determine the functional consequences of Dgkk deregulation in the mouse and humans, or its absence (new Dgkk-KO mouse model) and demonstrate that its deregulation is critical for FXS condition, 3) validate DGKk as a novel therapeutic target for FXS in the Fmr1-KO mouse model. The program will be performed by a consortium that combines a panel of expertise spanning RNA/protein interactions, lipid signaling, neuronal electrophysiology, and animal behavior. The main expected outcome will be a detailed molecular description of the molecular mechanism by which FMRP contributes to the control of local protein translation within neurons, the deregulation of which is causing the well-defined neurological alterations of the Fragile X syndrome. A second main expected outcome is the validation of a proof of concept for a novel therapeutic mean in the FXS mouse model.