Pyramidal cell types and 5-HT 2A receptors are essential for psilocybin’s lasting drug action
OpenAlex – November 03, 2024
Source: OpenAlex
Summary
Silencing specific brain cells can completely eliminate the therapeutic benefits of psilocybin. This hallucinogen, an alkaloid studied in psychedelics and drug studies, increases dendritic spine density in two pyramidal cell types. However, only subcortical-projecting (PT) neurons, when silenced, abolish the drug's action on stress-related behaviors. Psilocybin boosts synaptic activity and firing rates exclusively in PT neurons. This drug's action relies on the 5-HT2A receptor, a key neurotransmitter receptor influencing behavior. This neuroscience and pharmacology insight pinpoints PT cells and the 5-HT2A receptor as crucial for psilocybin's long-term effects.
Abstract
Abstract Psilocybin is a serotonergic psychedelic with therapeutic potential for treating mental illnesses 1–4 . At the cellular level, psychedelics induce structural neural plasticity 5,6 , exemplified by the drug-evoked growth and remodeling of dendritic spines in cortical pyramidal cells 7–9 . A key question is how these cellular modifications map onto cell type-specific circuits to produce psychedelics’ behavioral actions 10 . 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-HT 2A receptors abolishes psilocybin’s effects on stress-related behavior and structural plasticity. Collectively these results identify a pyramidal cell type and the 5-HT 2A receptor in the medial frontal cortex as playing essential roles for psilocybin’s long-term drug action.