Transient Stimulation with Psychoplastogens Is Sufficient to Initiate Neuronal Growth

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

ACS Pharmacology and Translational Science, 2020.

doi : 10.1021/acsptsci.0c00065

 

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.

KEYWORDS : neural plasticity, psychoplastogen, psychedelic, LSD, ketamine, BDNF

 

Depression is among the leading causes of disability worldwide, affecting over 300 million people.1,2 Current treatments, such as the selective serotonin reuptake inhibitor (SSRI) fluoxetine, are only moderately effective, require daily administration for 2−4 weeks before producing beneficial effects, and are associated with a number of side effects leading to discontinuation of treatment regimens.3,4 Moreover, approximately one-third of patients are unresponsive to these medicines,4 highlighting the urgent need for new treatment approaches. A better understanding of depression pathophysiology will be necessary to rationally devise more effective therapeutics.

In recent years, it has become clear that depression results from deleterious structural and functional changes in key brain circuits. These include the retraction of dendrites, the elimination of dendritic spines, and the loss of excitatory synapses in the prefrontal cortex (PFC).5−8 Psychoplastogens, small molecules that promote the rapid regrowth of atrophied cortical dendritic arbors,9 represent the leading edge of antidepressant neurotherapeutics. They include ketamine,10−13 scopolamine,14−17 and serotonergic psychedelics.18−25 These compounds rapidly promote structural and functional neural plasticity in the cortex26−28 and produce long-lasting (>24 h) changes in mood and behavior without the need for chronic dosing,29−34 presumably due to their ability to rewire pathological neural circuitry.

Induced plasticity (iPlasticity) has been proposed as a potential unifying mechanism to explain the efficacy of antidepressants from different chemical classes.35,36 Traditional antidepressants like fluoxetine are believed to promote cortical neuron growth through transactivation of the tropomyosin receptor kinase B (TrkB),37−39 the high-affinity receptor for brain-derived neurotrophic factor (BDNF). Psychoplastogens produce more rapid changes in cortical neuron structure, but their mechanisms of action are still opaque. Understanding how psychoplastogens produce enduring changes in cortical neuron structure, despite being rapidly cleared from the body, will be critical if we are to rationally engineer safer and more efficacious medicines for treating depression.

Previously, we demonstrated that psychedelics could increase cortical neuron growth when treated for extended periods of time (24−72 h). Here, we establish that very short stimulation periods (15 min to 6 h) are sufficient for ketamine and lysergic acid diethylamide (LSD), two psychoplastogens from distinct chemical classes, to initiate a neuronal growth response characterized by sustained α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid (AMPA) receptor and mammalian target of rapamycin (mTOR) activation. This response persists even after the removal of the stimulating ligand. Our results indicate that ketamine and serotonergic psychoplastogens may lead to enduring changes in neuronal structure through a common downstream mechanism of action. Moreover, our results have important implications for central nervous system (CNS) drug development, as they suggest that intentional engineering of neurotherapeutics to be rapidly cleared from the body might be an effective strategy for maintaining efficacy while minimizing side effects.

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