A reciprocal interplay between 5-HT2A and mGlu5 receptors underlies neuroplasticity
bioRxiv Preprint Server July 23, 2025 Tomas Del Olmo, Mathilde Decourcelle, Martial Séveno et al. preprint
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.