Transient Stimulation with Psychoplastogens Is Sufficient to Initiate Neuronal Growth
This in vitro study demonstrated that the psychoplastogens ketamine and LSD promote sustained cortical neuron growth, a process hypothesized to reverse atrophy associated with depression. The study finds that this growth occurs via two distinct phases involving initial TrkB activation followed by sustained mTOR and AMPA receptor activation.
Authors
- Maxemiliano Vargas
Published
Abstract
Cortical neuron atrophy is a hallmark of depression and includes neurite retraction, dendritic spine loss, and decreased synaptic density. Psychoplastogens, small molecules capable of rapidly promoting cortical neuron growth, have been hypothesized to produce long-lasting positive effects on behavior by rectifying these deleterious structural and functional changes. Here we demonstrate that ketamine and LSD, psychoplastogens from two structurally distinct chemical classes, promote sustained growth of cortical neurons after only short periods of stimulation. Furthermore, we show that psychoplastogen-induced cortical neuron growth can be divided into two distinct epochs: an initial stimulation phase requiring TrkB activation and a growth period involving sustained mTOR and AMPA receptor activation. Our results provide important temporal details concerning the molecular mechanisms by which next-generation antidepressants produce persistent changes in cortical neuron structure, and they suggest that rapidly excreted psychoplastogens might still be effective neurotherapeutics with unique advantages over compounds like ketamine and LSD.
Research Summary of 'Transient Stimulation with Psychoplastogens Is Sufficient to Initiate Neuronal Growth'
Introduction
Depression is associated with structural degeneration in prefrontal cortical circuits, including dendritic retraction, loss of dendritic spines, and reduced excitatory synapse density. Conventional antidepressants (for example selective serotonin reuptake inhibitors) require chronic dosing and have limited efficacy for many patients, prompting interest in agents that rapidly promote neural plasticity. Psychoplastogens—small molecules such as ketamine, scopolamine and serotonergic psychedelics—can rapidly stimulate regrowth of cortical dendritic arbors and produce relatively long-lasting behavioural effects after single administrations, but the biochemical sequence that allows a short pharmacological exposure to yield sustained structural change is not well defined. Ly and colleagues set out to determine whether very brief exposures to psychoplastogens are sufficient to initiate sustained growth of cortical neurons and to dissect the temporal requirements for key signalling nodes. Using ketamine and lysergic acid diethylamide (LSD) as representative psychoplastogens, the study tests how short stimulation periods (minutes to hours) affect dendritogenesis, spinogenesis and synaptogenesis in primary cortical cultures, and uses pharmacological inhibitors to probe roles for TrkB, AMPA receptors and mTOR during both the initial stimulation and the subsequent drug-free growth phase. The work aims to clarify mechanistic epochs underlying psychoplastogen-driven plasticity and to inform development of neurotherapeutics with rapid onset and reduced side effects.
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Study Details
- Study Typeindividual
- Journal
- Compounds
- Topic
- Author
- APA Citation
Ly, C., Greb, A. C., Vargas, M. V., Duim, W. C., Grodzki, A. C. G., Lein, P. J., & Olson, D. E. (2021). Transient Stimulation with Psychoplastogens Is Sufficient to Initiate Neuronal Growth. ACS Pharmacology & Translational Science, 4(2), 452-460. https://doi.org/10.1021/acsptsci.0c00065
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