A reciprocal interplay between 5-HT _2A and mGlu ₅ receptors underlies neuroplasticity

The serotonin (5-HT) _2A receptor is the primary target of numerous psychoactive drugs including serotonergic psychedelics, and mediates psychedelics-induced neuroplasticity, but the signaling mechanisms involved remain poorly characterized. Using quantitative phosphoproteomics, we show that the administration of the hallucinogenic 5-HT _2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) to mice promotes the phosphorylation of synaptic proteins belonging to a strongly interconnected protein network and comprising the metabotropic glutamate (mGlu) ₅ receptor and the scaffolding protein Shank3. Functional studies revealed that hallucinogenic and non-hallucinogenic 5-HT _2A receptor agonists promote synaptic targeting of mGlu ₅ receptor and its association with Shank3. Furthermore, they gate neuroplasticity in cortical neurons through a mechanism requiring mGlu ₅ receptor, protein kinase C and Shank3. Conversely, neuroplasticity elicited by mGlu ₅ receptor activation depends on 5-HT _2A receptor. Collectively, these findings demonstrate that neuroplasticity-promoting properties of psychedelics depend on a functional, reciprocal interplay between 5-HT _2A and mGlu ₅ receptors involving the synaptic scaffolding protein Shank3.