Psilocin fosters neuroplasticity in iPSC-derived human cortical neurons
Målin Schmidt, Anne Hoffrichter, Mahnaz Davoudi, Sandra Horschitz, Thorsten Lau, Marcus W. Meinhardt, Rainer Spanagel, Julia Ladewig, Georg Köhr, Philipp Koch
Research Square June 7, 2024 preprint DOI: 10.21203/rs.3.rs-4242829/v1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study |
|---|---|
| Population | Human cortical neurons derived from induced pluripotent stem cells |
| Intervention | psilocin |
| Topics | Neuroplasticity Psilocybin |
| Keywords | Cortical neurons |
| Citations | 5 |
| Key findings | Psilocin exposure induces enhanced neuronal plasticity in human cortical neurons, characterized by increased complexity, synaptic protein expression, and network activity. |
Abstract
Abstract Psilocybin is studied as innovative medication in anxiety, substance abuse and treatment-resistant depression. Animal studies show that psychedelics promote neuronal plasticity by strengthening synaptic responses and protein synthesis. However, the exact molecular and cellular changes induced by psilocybin in the human brain are not known. Here, we treated human cortical neurons derived from induced pluripotent stem cells with the 5-HT2A receptor agonist psilocin - the psychoactive metabolite of psilocybin. We analyzed how exposure to psilocin affects 5-HT2A receptor localization, gene expression, neuronal morphology, synaptic markers and neuronal function. Upon exposure of human neurons to psilocin, we observed a decrease of cell surface-located 5-HT2A receptors first in the axonal- followed by the somatodendritic-compartment. Psilocin further provoked a 5-HT2A-R-mediated augmentation of BDNF abundance. Transcriptomic profiling identified gene expression signatures priming neurons to neuroplasticity. On a morphological level, psilocin induced enhanced neuronal complexity and increased expression of synaptic proteins, in particular in the postsynaptic-compartment. Consistently, we observed an increased excitability and enhanced synaptic network activity in neurons treated with psilocin. In conclusion, exposure of human neurons to psilocin might induces a state of enhanced neuronal plasticity which could explain why psilocin is beneficial in the treatment of neuropsychiatric disorders where synaptic dysfunctions are discussed.