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 via bioRxiv
Summary
Psychedelic drugs like DOI trigger neuroplasticity in mouse brain cells through a reciprocal interaction between the serotonin 5-HT2A receptor and the metabotropic glutamate mGlu5 receptor, linked by the scaffolding protein Shank3. Phosphoproteomics showed that DOI increases phosphorylation of synaptic proteins including mGlu5 and Shank3. Both hallucinogenic and non-hallucinogenic 5-HT2A agonists promoted mGlu5's movement to synapses and its binding to Shank3. Neuroplasticity in cortical neurons required mGlu5, protein kinase C, and Shank3; conversely, mGlu5-driven plasticity depended on the 5-HT2A receptor. These findings demonstrate that psychedelics' neuroplasticity relies on a functional interplay between these two receptors and Shank3.
Study at a glance
| Characteristics | Experimental study |
|---|---|
| Population | Mice |
| Key finding | 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.