Pyramidal cell types and 5-HT2A receptors are essential for psilocybin’s lasting drug action
bioRxiv – November 02, 2024
Source: medRxiv/bioRxiv/arXiv
Summary
A single dose of psilocybin, a promising treatment for mental health issues, enhances the growth of specific brain cells linked to stress relief. Researchers discovered that one type of pyramidal cell is crucial for this effect, while a receptor called 5-HT2A is vital for psilocybin’s lasting benefits. This highlights the drug's transformative potential in therapy.
Abstract
Psilocybin is a serotonergic psychedelic with therapeutic potential for treating mental illnesses1–4. At the cellular level, psychedelics induce structural neural plasticity5,6, exemplified by the drug-evoked growth and remodeling of dendritic spines in cortical pyramidal cells7–9. A key question is how these cellular modifications map onto cell type-specific circuits to produce psychedelics’ behavioral actions10. Here, we use in vivo optical imaging, chemogenetic perturbation, and cell type-specific electrophysiology to investigate the impact of psilocybin on the two main types of pyramidal cells in the mouse medial frontal cortex. We find that a single dose of psilocybin increased the density of dendritic spines in both the subcortical-projecting, pyramidal tract (PT) and intratelencephalic (IT) cell types. Behaviorally, silencing the PT neurons eliminates psilocybin’s ability to ameliorate stress-related phenotypes, whereas silencing IT neurons has no detectable effect. In PT neurons only, psilocybin boosts synaptic calcium transients and elevates firing rates acutely after administration. Targeted knockout of 5-HT2A receptors abolishes psilocybin’s effects on stress-related behavior and structural plasticity. Collectively these results identify a pyramidal cell type and the 5-HT2A receptor in the medial frontal cortex as playing essential roles for psilocybin’s long-term drug action.