Xanthurenic and cinnabarinic acids: two kynurenine metabolites interacting with metabotropic glutamate receptors involved in schizophrenia and ultra-high risk for psychosis states

Alterations of the kynurenine pathway are linked to the pathophysiology of schizophrenia. Cinnabarinic acid (CA) is a kynurenine metabolite that activates mGlu4 metabotropic glutamate receptors. Its function in the CNS is largely unexplored. Moreover, xanthurenic acid (XA), produced by transamination of 3-hydroxykynurenines, was found to activate mGlu2 metabotropic glutamate receptors. Here, we have explored the interaction between XA and mGlu2/3 and between CA and mGlu4 receptors using in a battery of vivo models. Moreover, we assessed serum levels of kynurenine metabolites in a large cohort of patients affected by schizophrenia, their first-degree relatives, healthy controls and Ultra-High Risk (UHR) for psychosis subjects. Since CA was not detectable in serum of healthy controls, we measured CA levels in autoptic brain tissue of 23 individuals affected by schizophrenia and 26 age-matched controls.