Psilocybin's lasting action requires pyramidal cell types and 5-HT2A receptors

  • Nature. 2025 Jun;642(8067):411-420. doi: 10.1038/s41586-025-08813-6.
Ling-Xiao Shao  #  1  2 ,  Clara Liao  #  1  3 ,  Pasha A Davoudian  1  3  4 ,  Neil K Savalia  1  3  4 ,  Quan Jiang  1 ,  Cassandra Wojtasiewicz  1 ,  Diran Tan  1 ,  Jack D Nothnagel  1 ,  Rong-Jian Liu  2 ,  Samuel C Woodburn  1 ,  Olesia M Bilash  1 ,  Hail Kim  5 ,  Alicia Che  2 ,  Alex C Kwan  6  7  8
Affiliations
  • 1. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA.
  • 2. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
  • 3. Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, CT, USA.
  • 4. Medical Scientist Training Program, Yale University School of Medicine, New Haven, CT, USA.
  • 5. Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.
  • 6. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA. [email protected].
  • 7. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA. [email protected].
  • 8. Department of Psychiatry, Weill Cornell Medicine, New York, NY, USA. [email protected].
  • # Contributed equally.
PMID: 40175553 DOI: 10.1038/s41586-025-08813-6
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 remodelling of dendritic spines in cortical pyramidal cells7-9. A key question is how these cellular modifications map onto cell-type-specific circuits to produce the psychedelics' behavioural 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 increases the density of dendritic spines in both the subcortical-projecting, pyramidal tract (PT) and intratelencephalic (IT) cell types. Behaviourally, 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 behaviour and structural plasticity. Collectively, these results identify that a pyramidal cell type and the 5-HT2A receptor in the medial frontal cortex have essential roles in psilocybin's long-term drug action.

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