2. Academic Validation
  3. Psilocybin's lasting action requires pyramidal cell types and 5-HT2A receptors

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

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. alex.kwan@cornell.edu.
  • 7 Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA. alex.kwan@cornell.edu.
  • 8 Department of Psychiatry, Weill Cornell Medicine, New York, NY, USA. alex.kwan@cornell.edu.
  • # 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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