Transient Stimulation with Psychoplastogens Is Sufficient to Initiate Neuronal Growth

Calvin Ly, Alexandra C. Greb, Maxemiliano V. Vargas, Whitney C. Duim, Ana Grodzki, Pamela J. Lein, David E. Olson

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)452-460
Number of pages9
JournalACS Pharmacology and Translational Science
Volume4
Issue number2
DOIs
StatePublished - Apr 9 2021

Keywords

  • BDNF
  • ketamine
  • LSD
  • neural plasticity
  • psychedelic
  • psychoplastogen

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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