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.
Comparable studies
Other preclinical and animal studies on neuroplasticity, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| Psychedelics promote plasticity by directly binding to BDNF receptor TrkB Mice | 2023 | Experimental study | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study | |
| The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro Progenitor cells from subventricular and subgranular zones of adult mice brains | 2017 | In vitro experimental study | |
| N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo Mice | 2020 | In vitro and in vivo experimental study |
Citations in the library
Cites 25
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future. Neuropsychopharmacology April 26, 2017
- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
- A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 2021
and 20 more in the library