Pyramidal cell types and 5-HT2A receptors are essential for psilocybin’s lasting drug action

This pre-print mouse study investigates how psilocybin affects different types of brain cells in the medial frontal cortex (mPFC; decision-making processes and judgement). The research finds that psilocybin increases dendritic spine density in both pyramidal tract (PT) and intratelencephalic (IT) neurons, but only PT neurons are essential for psilocybin’s anti-stress effects through 5-HT2A receptor activation.

Abstract of Pyramidal cell types and 5-HT2A receptors are essential for psilocybin’s lasting drug action

“Psilocybin is a serotonergic psychedelic with therapeutic potential for treating mental illnesses. At the cellular level, psychedelics induce structural neural plasticity, exemplified by the drug-evoked growth and remodeling of dendritic spines in cortical pyramidal cells. A key question is how these cellular modifications map onto cell type-specific circuits to produce psychedelics’ behavioral actions. 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.“

Authors: Ling-Xiao Shao, Clara Liao, Pasha A. Davoudian, Neil K. Savalia, Quan Jiang, Cassandra Wojtasiewicz, Diran Tan, Jack D. Nothnagel, Rong-Jian Liu, Samuel C. Woodburn, Olesia M. Bilash, Hail Kim, Alicia Che & Alex C. Kwan

Summary of Pyramidal cell types and 5-HT2A receptors are essential for psilocybin’s lasting drug action

The study investigates the cellular effects of psilocybin, a psychedelic compound, focusing on its long-lasting structural changes in brain cells and potential therapeutic implications for mental health conditions. Psilocybin, which has shown clinical promise in treating depression, is hypothesised to work through mechanisms that enhance neural plasticity, specifically in pyramidal neurons in the brain’s medial frontal cortex. Pyramidal neurons play critical roles in brain connectivity and are categorised mainly into two types: pyramidal tract (PT) neurons, which project to subcortical regions, and intratelencephalic (IT) neurons, which project within the cerebral cortex. Both PT and IT neurons have distinct properties and connect to different brain circuits.

While previous studies suggest psychedelics increase dendritic spine density—small, protruding structures on neurons that are essential for synaptic transmission and plasticity—the cellular and circuit-specific actions of psilocybin remain unclear. In this study, the researchers explored how psilocybin impacts PT and IT neurons in the medial frontal cortex of mice, focusing on dendritic spine changes and behavioural effects. They also examined the role of the 5-HT2A serotonin receptor, which is central to psychedelic effects, to see if it mediates psilocybin-induced changes in both neuron types.

Cell-Type Specificity in Psilocybin-Induced Structural Plasticity

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Find this paper

Pyramidal cell types and 5-HT2A receptors are essential for psilocybin's lasting drug action

https://doi.org/10.1101/2024.11.02.621692

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Cite this paper (APA)

Shao, L. X., Liao, C., Davoudian, P. A., Savalia, N. K., Jiang, Q., Wojtasiewicz, C., ... & Kwan, A. C. (2024). Pyramidal cell types and 5-HT2A receptors are essential for psilocybin's lasting drug action. bioRxiv, 2024-11.

Study details

Compounds studied
Psilocybin

Topics studied
Neuroscience

Study characteristics
Animal Study Bio/Neuro

Compound Details

The psychedelics given at which dose and how many times

Psilocybin 1 mg | 1x

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