Cell-type specific transcriptional modulation by psilocybin induces sustained plasticity in mouse medial prefrontal cortex
Delong Zhou, Heike Schuler, Vedrana Cvetkovska, Juliet Meccia, Ashot S. Harutyunyan, Jiannis Ragoussis, Rosemary C. Bagot, Ashot S. Harutyunyan, Jiannis Ragoussis, Danilo Bzdok, Rosemary C. Bagot
bioRxiv (Cold Spring Harbor Laboratory) January 8, 2025 preprint DOI: 10.1101/2025.01.08.631940 via OpenAlex
Summary
AI-generated from the abstractA single dose of psilocybin increases synaptic transmission in the medial prefrontal cortex of mice. Single-cell RNA sequencing reveals that, 24 hours after administration, plasticity-related gene expression rises in excitatory neurons, with particularly robust changes in a deep-layer neuron type called L5/6 NP. This cell-type specificity aligns with 5-HT 2C receptor expression patterns, not 5-HT 2A. Multivariate analyses show that psilocybin-induced gene expression in L5/6 NP neurons predicts 5-HT 2C transcript levels. Blocking 5-HT 2C receptors with an antagonist attenuates the sustained effect on synaptic transmission, identifying 5-HT 2C signaling and L5/6 NP neurons as key mediators of psilocybin's lasting neuroplastic effects.
Study at a glance
| Characteristics | Experimental study |
|---|---|
| Population | Mice |
| Intervention | Psilocybin |
| Dose | single dose |
| Duration | 24 hours post-psilocybin |
| Topics | Neuroplasticity Psilocybin |
| Keywords | Prefrontal cortex Neuroscience Cell type |
| Citations | 2 |
| Key finding | Psilocybin's sustained neuroplastic effects in the mouse medial prefrontal cortex are mediated by 5-HT 2C signaling and L5/6 NP neurons. |
Abstract
Abstract Despite enormous interest in psychedelics for psychiatric interventions, potential underlying biological mechanisms remain unclear. Here, we confirm that a single dose of psilocybin increases synaptic transmission in mouse medial prefrontal cortex. Using scRNA-sequencing, we identify cell-type specific mechanisms of sustained neuroplastic effects. We show that, 24h post-psilocybin, expression of plasticity-related genes is increased in excitatory neurons and that transcription in a type of deep layer near projecting neuron, L5/6 NP, is robustly altered. Analyzing receptor expression patterns reveals that this cell-type specificity does not align with 5-HT 2A expression but aligns with 5-HT 2C expression patterns. Further, multivariate analyses identify psilocybin-induced gene expression patterns in L5/6 NP neurons predict 5-HT 2C , but not 5-HT 2A , transcript levels. Pharmacologic manipulation with a 5-HT 2C antagonist attenuates the post-acute sustained effect of psilocybin on synaptic transmission, highlighting 5-HT 2C signaling and L5/6 NP neurons as key mediators of psychedelic drug action’s sustained neuroplastic effects in mPFC.