mGlu2 Receptor Signaling in the Brain: Alterations in Preclinical Models for schizophrenia and Interference between Antipsychotics – SchizoGlu

Schizophrenia affects 1% of the world population. Current treatments poorly control symptoms and induce side effects. A promising new generation of antipsychotics that activate metabotropic glutamate receptor 2 is under clinical trial but first molecules failed due to inference with broadly prescribed atypical antipsychotics inhibiting serotonin 2A receptor. If mGlu2 molecules are still good candidates as first-line treatment, this raised some important questions and mGlu2 receptor signaling in the brain remains poorly characterized. Thus, the project will rely on state of the art functional proteomics and original mGlu2 nanobodies (monocatenar Llama antibodies) to 1) decipher mGlu2 signaling in mice brain, with the hope of finding new regulators and new effectors different from the canonical Gaio protein / adenylate cyclase / cAMP pathway or ßarrestin pathway, 2) determine the alterations of new effectors and regulators in well-established preclinical models for schizophrenia, 3) determine the effect of 5-HT2A receptor chronic inhibition on mGlu2 receptor effectors to understand the interference between new generation of antipsychotics targeting mGlu2 receptor and atypical antipsychotics, 4) determine the importance of new regulators and effectors in the capacity of mGlu2 receptor to respond to stimulation and to correct behavioral defects in preclinical models for schizophrenia. Altogether, the project should provide important insights in the mechanism of action of last generation antipsychotics and the origin of the interference with atypical antipsychotics.