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

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Psilocybin is a serotonergic psychedelic with therapeutic potential for treating mental illnesses[1][1]–[4][2]. At the cellular level, psychedelics induce structural neural plasticity[5][3],[6][4], exemplified by the drug-evoked growth and remodeling of dendritic spines in cortical pyramidal cells[7][5]–[9][6]. A key question is how these cellular modifications map onto cell type-specific circuits to produce psychedelics’ behavioral actions[10][7]. 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. ### Competing Interest Statement A.C.K. has been a scientific advisor or consultant for Boehringer Ingelheim, Empyrean Neuroscience, Freedom Biosciences, and Psylo. A.C.K. has received research support from Intra-Cellular Therapies. The other authors report no financial relationships with commercial interests. [1]: #ref-1 [2]: #ref-4 [3]: #ref-5 [4]: #ref-6 [5]: #ref-7 [6]: #ref-9 [7]: #ref-10

Pyramidal cell types and 5-HT2A receptors are essential for psilocybin’s lasting drug action | bioRxiv Skip to main content New Results Pyramidal cell types and 5-HT 2A receptors are essential for psilocybin’s lasting drug action View ORCID Profile Ling-Xiao Shao , View ORCID Profile Clara Liao , View ORCID Profile Pasha A. Davoudian , View ORCID Profile Neil K. Savalia , View ORCID Profile Quan Jiang , Cassandra Wojtasiewicz , Diran Tan , Jack D. Nothnagel , Rong-Jian Liu , View ORCID Profile Samuel C. Woodburn , View ORCID Profile Olesia M. Bilash , View ORCID Profile Hail Kim , View ORCID P

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