Cell-type specific transcriptional modulation by psilocybin induces sustained plasticity in mouse medial prefrontal cortex
OpenAlex – January 08, 2025
Source: OpenAlex
Summary
A single dose of psilocybin dramatically enhances communication within the prefrontal cortex, a key brain region for memory and neural mechanisms. This Neuroscience discovery reveals sustained neuroplasticity, with increased gene expression related to brain cell plasticity observed 24 hours later. Specifically, a deep layer neuron cell type, L5/6 NP, drives this biology. Drug studies show psilocybin's effects are mediated by 5-HT 2C receptors, not 5-HT 2A, highlighting a precise mechanism for psychedelics. This cell-type specific action offers new insights into neuroendocrine regulation and behavior.
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.