Serotonergic Psychedelics Rapidly Modulate Evoked Glutamate Release in Cultured Cortical Neurons

Petrušková A, Guhathakurta D, Akdas EY, Perelló Amorós B, Frischknecht R, Weiss EM, Páleníček T, Fejtová A (2025)

Publication Language: English

Publication Type: Journal article

Publication year: 2025

Journal

Journal of Neurochemistry Wiley-Blackwell

Book Volume: 169

Article Number: e70020

Journal Issue: 3

DOI: 10.1111/jnc.70020

Abstract

The serotonergic psychedelics psilocybin, LSD and DMT hold great promise for the development of new treatments for psychiatric conditions such as major depressive disorder, addiction and end-of-life anxiety. Previous studies in both animals and humans have confirmed the effects of these drugs on neuronal activity and plasticity. However, the understanding of the mechanisms of action of these substances is limited. Here we show rapid effects of psychedelics on presynaptic properties, using live cell imaging at the level of single synapses in primary rat cortical neurons. Using the genetically encoded reporter of synaptic vesicle fusion synaptopHluorin, we detected a reduced fraction of synaptic vesicles that fused in response to mild or strong electrical stimulation 3–30 min after application of serotonergic psychedelics. These effects were transient and no longer present 24 h after treatment. While DMT only reduced the total recycling pool, LSD and psilocin also reduced the size of the readily releasable vesicle pool. Imaging with the sensors for glutamate, iGluSnFR, and presynaptic calcium, synGCaMP6, showed that while psilocin and DMT increased evoked glutamate release, LSD and psilocin reduced evoked presynaptic calcium levels. Interestingly, psilocin also affected short-term plasticity leading to a depression of responses to paired stimuli. The rapid and drug-specific modulation of glutamatergic neurotransmission described in this study may contribute to distinct anxiolytic and antidepressant properties of serotonergic psychedelics. (Figure presented.).

Authors with CRIS profile

Aneta Petrušková Department of Psychiatry and Psychotherapy Debarpan Guhathakurta Department of Psychiatry and Psychotherapy Enes Yagiz Akdas Department of Psychiatry and Psychotherapy Bartomeu Perelló Amorós Lehrstuhl für Tierphysiologie Renato Frischknecht Lehrstuhl für Tierphysiologie Eva-Maria Weiss Department of Psychiatry and Psychotherapy Anna Fejtová Professur für Molekulare Psychiatrie

Involved external institutions

National Institute of Mental Health (NIMH) / Národní ústav duševního zdraví (NUDZ) CZ Czech Republic (CZ)

How to cite

APA:

Petrušková, A., Guhathakurta, D., Akdas, E.Y., Perelló Amorós, B., Frischknecht, R., Weiss, E.-M.,... Fejtová, A. (2025). Serotonergic Psychedelics Rapidly Modulate Evoked Glutamate Release in Cultured Cortical Neurons. Journal of Neurochemistry, 169(3). https://doi.org/10.1111/jnc.70020

MLA:

Petrušková, Aneta, et al. "Serotonergic Psychedelics Rapidly Modulate Evoked Glutamate Release in Cultured Cortical Neurons." Journal of Neurochemistry 169.3 (2025).

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