{"doi":"10.1101/2024.11.02.621692","title":"Pyramidal cell types and 5-HT <sub>2A</sub> receptors are essential for psilocybin’s lasting drug action","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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":505662,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9576,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":256509,"name":"Clara Liao","orcid":"0000-0003-2734-8202","position":1,"is_corresponding":false},{"id":375812,"name":"Pasha A. Davoudian","orcid":"0000-0002-5096-7610","position":2,"is_corresponding":false},{"id":615529,"name":"Neil K. Savalia","orcid":"0000-0003-2262-4466","position":3,"is_corresponding":false},{"id":663338,"name":"Quan Jiang","orcid":"0000-0001-8201-6417","position":4,"is_corresponding":false},{"id":1331424,"name":"Cassandra Wojtasiewicz","orcid":null,"position":5,"is_corresponding":false},{"id":1356830,"name":"Diran Tan","orcid":null,"position":6,"is_corresponding":false},{"id":1356831,"name":"Jack D. Nothnagel","orcid":null,"position":7,"is_corresponding":false},{"id":1356512,"name":"Rongjian Liu","orcid":"0000-0003-4946-6859","position":8,"is_corresponding":false},{"id":614958,"name":"Samuel C. Woodburn","orcid":"0000-0001-9762-4335","position":9,"is_corresponding":false},{"id":790905,"name":"Olesia M. Bilash","orcid":"0000-0002-8157-3139","position":10,"is_corresponding":false},{"id":310408,"name":"Hail Kim","orcid":"0000-0002-6652-1349","position":11,"is_corresponding":false},{"id":1220618,"name":"Alicia Che","orcid":"0000-0002-7530-8531","position":12,"is_corresponding":false},{"id":459946,"name":"Alex C. Kwan","orcid":"0000-0003-2169-1667","position":13,"is_corresponding":false},{"id":616999,"name":"Ling-Xiao Shao","orcid":null,"position":0,"is_corresponding":true}],"reference_count":75,"raw_metadata":null,"created_at":"2026-07-19T02:10:47.170978Z","pmid":"39554087","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}