Robust Methods For Quantifying Neuronal Morphology And Molecular Signaling Reveal That Psychedelics Do Not Induce Neuroplasticity
Umed Boltaev, Hyun W. Park, Keaon R. Brown, Maya Delgado, Jorryn Wu, Brianna N. Diaz-pacheco, Maria Botero Pinzon, Keer He, Erin Ahern, Nina Goldshmid, Eleanor H. Simpson, Dalibor Sames
bioRxiv Preprint Server March 4, 2024 preprint DOI: 10.1101/2024.03.04.583022 via bioRxiv
Summary
Psychedelics do not directly influence the TrkB receptor or BDNF-TrkB signaling in primary neuronal cultures, contradicting previous findings. The study shows low levels of 5HT2a receptor gene expression and functional receptors, with no morphological growth induced by psychedelics, unlike the significant dendritogenesis seen with BDNF. These results emphasize the need for more rigorous methods in studying neuroplasticity effects of both established and experimental therapeutics.
Study at a glance
| Population | primary neuronal cultures |
|---|---|
| Key finding | Psychedelics do not induce morphological growth in primary neuronal cultures and do not directly modulate TrkB receptor or BDNF-TrkB signaling. |
Abstract
Induction of neuroplasticity has become the dominant explanatory framework for the rapid and sustained therapeutic effects of classic psychedelics. Within this broad concept, examination of morphological neuronal plasticity, such as dendritic arbor growth, is widely used to assess the neuroplasticity effects of classic and novel psychedelics. At the molecular level, it has been reported that serotonergic psychedelic compounds mediate dendritogenesis via the master molecular regulator of plasticity, TrkB, either directly via BDNF/TrkB signaling potentiation or indirectly through 5-HT2A receptor. To examine these hypotheses in detail, we developed a robust multimodal screening platform for unbiased, semi-automated quantification of cellular morphology and multiplex molecular signaling in the same cortical neurons. We found that in widely used primary neuronal cultures psychedelics do not directly modulate TrkB receptor or BDNF-TrkB signaling. We also found 5HT2a receptor gene expression and functional receptor levels are low, and psychedelics do not induce morphological growth, in contrast to significant dendritogenesis elicited by BDNF. Our results challenge recently published results in the field and indicate a need for rigorous experimental methods to study morphological manifestations of neuroplasticity effects induced by clinically used and experimental therapeutics.