Highlights d UCMS induces changes in the GM d GM from UCMS mice induces depression and decreases HpC neurogenesis in healthy mice d GM from UCMS mice impairs the serotonergic pathway of Trp metabolism d Promoting 5-HT biosynthesis alleviates the symptoms of GMinduced depression

The serotonin 5-HT and glutamate mGlu receptors continue to attract particular attention, given their implication in psychosis associated with schizophrenia and the mechanism of action of atypical antipsychotics and a new class of antipsychotics, respectively. A large body of evidence indicates a functional crosstalk between both receptors in the brain, but the underlying mechanisms are not entirely elucidated. Here, we have explored the influence of 5-HT receptor upon the phosphorylation pattern of mGlu receptor in light of the importance of specific phosphorylation events in regulating G protein-coupled receptor signaling and physiological outcomes. Among the five mGlu receptor-phosphorylated residues identified in HEK-293 cells, the phosphorylation of Ser was enhanced upon mGlu receptor stimulation by the orthosteric agonist LY379268 only in cells co-expressing the 5-HT receptor. Likewise, administration of LY379268 increased mGlu receptor phosphorylation at Ser in prefrontal cortex of wild-type mice but not 5-HT mice. Exposure of HEK-293 cells co-expressing mGlu and 5-HT receptors to 5-HT also increased Ser phosphorylation state to a magnitude similar to that measured in LY379268-treated cells. In both HEK-293 cells and prefrontal cortex, Ser phosphorylation elicited by 5-HT receptor stimulation was prevented by the mGlu receptor antagonist LY341495, while the LY379268-induced effect was abolished by the 5-HT receptor antagonist M100907. Mutation of Ser into alanine strongly reduced G signaling elicited by mGlu or 5-HT receptor stimulation in cells co-expressing both receptors. Collectively, these findings identify mGlu receptor phosphorylation at Ser as a key molecular event that underlies the functional crosstalk between both receptors.