Transient Stimulation with Psychoplastogens Is Sufficient to Initiate Neuronal Growth

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.

Automated summary

Cortical neuron atrophy is a hallmark of depression, and psychoplastogens like ketamine and LSD have been shown to promote sustained growth of cortical neurons after short periods of stimulation. These psychoplastogens induce cortical neuron growth through distinct phases, with early TrkB activation and later sustained mTOR and AMPA receptor activation being crucial. It is suggested that rapidly excreted psychoplastogens may have unique advantages as neurotherapeutics compared to compounds like ketamine and LSD.