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

• 成果类型: Article
• 署名作者: Shao, Ling-Xiao; Liao, Clara; Davoudian, Pasha A.; Savalia, Neil K.; Jiang, Quan; Wojtasiewicz, Cassandra; Tan, Diran; Nothnagel, Jack D.; Liu, Rong-Jian; Woodburn, Samuel C.; Bilash, Olesia M.; Kim, Hail; Che, Alicia; Kwan, Alex C.
• 署名单位: Cornell University; Yale University; Yale University; Yale University; Korea Advanced Institute of Science & Technology (KAIST); Cornell University; Weill Cornell Medicine
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1899
• DOI: 10.1038/s41586-025-08813-6
• 发表日期: 2025-06-12
• 关键词: medial prefrontal cortex; long-term; dendritic spines; modulation; FRAMEWORK; circuit; neurons

摘要

Psilocybin is a serotonergic psychedelic with therapeutic potential for treating mental illnesses1, 2, 3-4. 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, 8-9. 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.