Transient Stimulation with Psychoplastogens Is Sufficient to Initiate Neuronal Growth
Calvin Ly, Alexandra C. Greb, Maxemiliano V. Vargas, Whitney C. Duim, Ana Cristina Grodzki, Pamela J Lein, David E. Olson
ACS Pharmacology & Translational Science September 11, 2020 DOI: 10.1021/acsptsci.0c00065 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Cortical neurons |
| Interventions | Ketamine LSD |
| Keywords | Stimulation Ampa receptor Neurite Cortical neurons Glutamate receptor |
| Citations | 127 |
| Key findings | Ketamine and LSD promote sustained growth of cortical neurons after short stimulation, with growth divided into an initial TrkB-dependent stimulation phase and a later mTOR- and AMPA receptor-dependent growth period. |
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.