Grant: Project Grant

Most pharmacological principles used in psychiatry have been discovered by serendipity in the 1950s and 60s. Identification of the primary targets of these first generation drugs has led to an explosion of psychopharmacology blockbusters in the late 20th century. However, psychiatric drug development has since stalled mostly due to a lack of significant new drug targets. Mood stabilizers like lithium are drugs used to manage bipolar disorder, an important mental illness affecting 2% of the population. Mood stabilizers exert some of their therapeutic action by inhibiting the serine threonine kinase Glycogen synthase kinase 3 beta (GSK3). Pharmacological inhibition of GSK3 has thus become an important new strategy for the treatment of mental illnesses. However, several limitations associated to the specificity and long-term toxicity of GSK3 inhibitors remain serious obstacles. We have identified FXR1P, an RNA binding protein of the fragile X family, as a new substrate of GSK3 implicated in the behavioral actions of psychiatric drugs. We propose to examine the regulation of FXR1P by GSK3 and its implications in the action of mood stabilizers. This project will involve 1- The characterization of the role played by FXR1P in the effects of psychiatric drugs. 2-The identification of targets of FXR1P involved in this effect. 3-the elucidation of the mechanisms by which FXR1P contributes to the regulation of behavior. Research conducted within this project will allow tackling the contribution of FXR1P to the action of mood stabilizers. This will result in a better understanding of the action of existing psychoactive compounds and provide new avenues for the development of more effective approaches for the treatment of bipolar disorders.