A reciprocal interplay between 5-HT2A and mGlu5 receptors underlies neuroplasticity
Tomas Del Olmo, Mathilde Decourcelle, Martial Séveno, Joël Bockaert, Philippe Marin, Carine Bécamel
bioRxiv Preprint Server July 23, 2025 preprint DOI: 10.1101/2025.07.23.666382 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study |
|---|---|
| Population | Mice |
| Topics | Neuroplasticity Serotonin |
| Key findings | Psychedelics promote neuroplasticity through a reciprocal interplay between the 5-HT2A and mGlu5 receptors involving the scaffolding protein Shank3. |
Abstract
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-HT2A 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-HT2A receptor agonists promote synaptic targeting of mGlu5 receptor and its association with Shank3. Furthermore, they gate neuroplasticity in cortical neurons through a mechanism requiring mGlu5 receptor, protein kinase C and Shank3. Conversely, neuroplasticity elicited by mGlu5 receptor activation depends on 5-HT2A receptor. Collectively, these findings demonstrate that neuroplasticity-promoting properties of psychedelics depend on a functional, reciprocal interplay between 5-HT2A and mGlu5 receptors involving the synaptic scaffolding protein Shank3.