title: The psychedelic psilocin fosters neuroplasticity in iPSC-derived human cortical neurons
creator: Schmidt, Malin
subject: ddc-500
subject: 500 Natural sciences and mathematics
subject: ddc-570
subject: 570 Life sciences
description: Psychedelics have the fascinating potential to induce altered states of consciousness. First promising research for their therapeutical application stopped in the early 70’s when psychedelics were criminalized. Since the 90’s psychedelic research is regaining revival. On the one hand new psychopharmacological entities are urgently needed because the number of patients suffering from psychiatric disorders is constantly increasing and novel drug release is declining. Justified one the other hand by the broad therapeutical potential in psychiatric disorders and the rapid and long-lasting effects, often described after just a single administration. Psychedelics might act here as “psychoplastogens”, which means that they have neuroplasticity-promoting effects. They might restore synaptic and neuronal dysfunctions, associated with psychiatric disorders, by generating a plastic cellular state in which remodulations and “brain network resetting” are likely. Support for that theory comes until now from animal research. One key candidate amongst the class of serotonergic psychedelics, named because they target the 5-HT2A serotonin receptor, is psilocybin. Psilocybin, the compound of hallucinogenic fungi, often referred as “magic mushrooms”, is intensively investigated in the treatment of depression, anxiety, obsessive-compulsive disorder and substance abuse disorder.   In this doctoral thesis I first employed human induced pluripotent stem cell-derived cortical neurons for deciphering the effects and therapeutic mode of action of psilocybin. I can show that psilocin (the active metabolite of psilocybin) leads to neuroplastic, morphological and functional changes that start shortly after administration and become manifested in time, such as synaptogenesis. As one of many findings, I can first show a subacute downregulation of the 5-HT2A receptor after psilocin administration, a mechanism well-known to prevent an overshooting of the serotonergic signaling. A normalization provides an explanation for the antidepressant mode of action in depression, where an increased 5-HT2A receptor density is described. Remarkably, psilocin further directly targets main components and associates of the plasmin-generating annexin A2 – S100A10 complex which are on their own key candidates in antidepressant drug response. Not only the core proteins of the complex annexin A2 and p11 as docking station for plasminogen, the precursor of plasmin but also plasminogen-cleaving enzymes were upregulated. But moreover, this complex mediates the cleavage of precursor (pro)-BDNF into mature (m)-BDNF in the brain. In line with that I can first replicate that psilocin increases neurotrophic key factor BDNF and its associated downstream pathways which are linked to neuronal survival and plasticity in a human in vitro system. Second, I can first show that psilocin leads to an elevated cleavage of pro-BDNF in m-BDNF. That finding is of paramount importance because recent studies show that actually an imbalance of the pro-BDNF into m-BDNF cleavage, resulting in reduced m-BDNF levels might be more important in depression pathophysiology than total BDNF level reductions.   My doctoral thesis suggests that exposure of human neurons to psilocin provokes a dynamic cascade which induces a state of enhanced neuronal plasticity. That neuroplasticity booster alone could explain why psilocin is effective in the treatment of neuropsychiatric disorders. But moreover, I can directly provide a novel explanation for the antidepressant mode of action of psilocybin. I first describe with the annexin A2 – S100A10 complex a new highly potent drug target for the treatment of psychiatric disorders that paves the way for the development of new antidepressant entities.
date: 2024
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/33215/1/Malin%20Schmidt_Dissertation_%202023.pdf
identifier: DOI:10.11588/heidok.00033215
identifier: urn:nbn:de:bsz:16-heidok-332151
identifier:   Schmidt, Malin  (2024) The psychedelic psilocin fosters neuroplasticity in iPSC-derived human cortical neurons.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/33215/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng