A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics

This opinion article (2021) postulates that ketamine and psychedelics substances enact their rapid fast-acting antidepressant effects by means of promoting neuroplasticity in a heterogeneous manner, by enhancing or suppressing dendritic excitability across different parts of the cellular membrane. Although precise measurements of this pharmacological effect across the entire dendritic tree are currently still lacking, the authors hypothesize that the spatial mismatches in the opposing effects of these drugs drive neuroplasticity at specific dendritic hotspots, depending on the microcircuitry of their respective target neurons.

Abstract

“Review: Ketamine can relieve symptoms of depression and anxiety, therefore filling a critically unmet psychiatric need. A few small-scale clinical studies suggest serotonergic psychedelics may have similar therapeutic effects. Ketamine may both enhance and suppress dendritic excitability, through microcircuit interactions involving disinhibition. Serotonergic psychedelics may both enhance and suppress excitability, through targeting coexpressed receptors. Spatial mismatch in the opposing drug actions on dendritic excitability is predicted to steer plasticity actions towards certain synapses and cell types. We present a dendrite-focused framework as a novel lens to view the actions of ketamine and serotonergic psychedelics on cortical circuits.”

Authors: Neil K. Savalia, Ling-Xiao Shao & Alex C. Kwan

Summary

Pilot studies have suggested that serotonergic psychedelics such as psilocybin may relieve depression. Ketamine, another psychotomimetic compound, may also promote neural plasticity, and may also enhance and suppress membrane excitability.

Towards a Shared Basis for Rapid-Acting Antidepressants

Psychedelics are compounds that produce an atypical state of consciousness characterized by altered perception, cognition, and mood. Ketamine, a dissociative, relieves depression with rapid onset and sustained positive effects, and has been approved for use as a nasal spray.

Psychedelic drugs have a short half-life, yet they promote neural plasticity and last for weeks. This is because they increase the expression of neurotrophic factors, which in turn increases the formation rate of new dendritic spines.

Ketamine and serotonergic psychedelics have similar effects on neural and behavioral consequences, but they act on different molecular targets. We propose that spatial mismatches in the opposing actions may account for the plasticity-promoting capacities of the drugs as well as their cell-type and brain-region specificity.

Ketamine, serotonergic psychedelics, and potentially other drugs with rapid-acting antidepressant effects may modulate dendritic excitability through idiosyncratic ligand – receptor interactions, driving local gradients of Ca2+ influx that drive neurotrophic factors and biochemical cascades to bias certain synapses for the favorable effects of long-term neural plasticity.

Ketamine, a noncompetitive NMDAR antagonist, reduces dendritic excitability by decreasing the open time and frequency of NMDARs, and traps the compound in a closed channel until the receptor is reopened by an agonist.

Ketamine antagonizes NMDARs on pyramidal neurons and GABAergic inhibitory neurons, and this results in a loss of inhibition on the cell body. This is consistent with the disinhibition framework of NMDAR antagonism.

A recent study demonstrated that ketamine increases synaptic excitability by decreasing inhibition mediated by somatostatin-expressing (SST) GABAergic interneurons. This suggests that ketamine’s direct and indirect effects on dendritic excitability may be opposing.

Serotonergic Psychedelics – Competition for Dendritic Excitability through Coexpressing Receptors

Serotonergic psychedelics, also referred to as serotonergic hallucinogens, have high affinity for serotonin (5-HT) receptors and engage a wide range of intracellular signal transduction pathways that can influence neuronal excitability.

5-HT2A and 5-HT1A receptors have contrasting effects on neuronal excitability, and are located in the frontal cortex. They compete with each other for activation, and a 5-HT2A or 5-HT1A receptor-specific antagonist can diminish the excitatory or suppressive component respectively.

Although 5-HT1A and 5-HT2A receptors can be present in the same pyramidal neurons, their subcellular localization appears to differ. 5-HT2A receptors are located in the proximal apical dendrite of pyramidal neurons in rat and macaque frontal cortex.

There is less consensus on the subcellular localization of 5-HT1A receptors, but what is clear is that 5-HT1A agonism decreases membrane excitability.

Multiple lines of evidence suggest ketamine and serotonergic psychedelics exert competing actions on dendritic excitability. The proposed opposing actions could account for some of the neural and behavioral features of these drugs.

Acute drug actions on dendritic excitability and Ca2+ influx are important contributors to long-term neural plasticity. These actions are mediated by the neurotrophic model for stress-related mood disorders and antidepressant actions.

Ketamine and serotonergic psychedelics are expected to initiate plasticity through their actions on dendritic excitability. However, the exact location of these actions on the dendritic tree remains open for experimental confirmation.

Although a full picture of each drug’s actions on dendrites is lacking, experiments show that local control of dendritic excitability can sculpt Ca2+ signaling and plasticity. Ketamine and serotonergic psychedelics may target different forms of dendritic Ca2+ signaling to affect plasticity.

We focused on dendritic locations with increased excitability, but ketamine reduces the propagation of electrical signals from the apical dendritic tuft to the cell body of layer 5 pyramidal neurons.

Opposing Actions as a Mechanism to Acutely Alter Synaptic Integration

Ketamine and serotonergic psychedelics acutely perturb dendritic excitability, which is tuned by homeostatic mechanisms that can calibrate excitability in a branch-specificmanner or even at the level of local GABAergic inputs. This impairs dendrites’ ability to receive and filter inputs, leading to warped awareness of the surroundings.

Subanesthetic ketamine may induce cognitive rigidity by causing perseverative deficits in the Wisconsin Card Sorting Task, but this effect is absent when subjects merely have to re-implement a learned rule.

Ketamine and serotonergic psychedelics act on the medial frontal cortex more than other brain regions, possibly because of their neural plasticity and because of their high metabolic activity in certain brain regions.

Ketamine activates pyramidal cells at the apical dendrites due to interneuron-mediated disinhibition. Regions with high abundance of SST interneurons relative to the overall inhibitory tone are more susceptible to ketamine-induced dendritic disinhibition, compared to motor regions.

The ratio of 5-HT1A to 5-HT2A receptors in the frontal cortex, entorhinal cortex, temporal cortex, and insula might determine the regional selectivity of serotonergic psychedelics. In mice, prefrontal regions tend to have a higher Htr2a:Htr1a expression ratio than posterior cortical regions.

There are numerous subtypes of pyramidal neurons in the frontal cortex, and each subtype’s response to ketamine and serotonergic psychedelics may depend on its sensitivity to the hypothesized opposing actions. There are many anatomical and molecular differences that could contribute to differential sensitivity across subtypes of pyramidal neurons.

We used a public database of single-cell RNA sequencing data from >10 000 cells sampled from the anterolateral motor cortex in mice to visualize the expression of 5-HT receptor subtypes in different cell types. We found that IT neurons have enriched expression of Htr2a, suggesting they are susceptible to psychedelic-induced increases in membrane excitability.

Opposing Actions as a Mechanism to Mitigate Toxicity

Although transient imbalance in dendritic excitability can promote plasticity, prolonged and excessive alterations may be deleterious and underpin various neuropsychiatric disorders.

Ketamine and serotonergic psychedelics have concurrent push-and-pull actions that influence dendritic excitability. At low doses, the excitatory actions can exceed inhibitory effects to generate maximal increase in dendritic excitability for the compound, safeguarding against high-intensity responses associated with drug toxicity.

Nonselective pharmacological therapies are appealing because they may generate a summative therapeutic action, while limiting adverse effects.

Box 1. Future Work Informed by the Dendritic Framework

The dendritic framework has gaps and predictions that compel further study. Serotonergic psychedelics can inhibit spontaneous activity in subcortical nuclei, contributing to the unique subjective effects of these compounds.

Ketamine and serotonergic psychedelics may open a critical window of plasticity in the frontal cortex, with concomitant inputs from other regions strengthening specific long-range pathways. This may suggest that purposeful, pathway-specific stimulation during the acute phase of drug administration could be beneficial.

For serotonergic psychedelics, new insights might be gained by characterizing the relative expression of 5-HT receptor subtypes, rather than their absolute abundances, in relation to dendritic responses, neural pathways, and behavioral outcomes. For ketamine, new imaging approaches may help address the nature of the predicted spatial mismatches in dendritic excitability.

Figure 2 shows the expression of Sst, Pvalb, Htr1a, and Htr2a in the adult mouse neocortex. The expression of these genes is inversely related to cortical hierarchy.

Ketamine has additional intriguing characteristics and off-target effects, but they generally align with the hypothesized push and pull on dendritic excitability. Moreover, the metabolite hydroxynorketamine has been shown to mediate rapid antidepressant-like effects without antagonizing NMDARs.

The 5-HT receptor signaling is complex, and the pharmacological features distinguishing psychedelics from other 5-HT-related agents are not well understood. However, the selective 5-HT2A agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) may promote neurite growth in cortical neurons and exert anxiolytic action without agonizing 5-HT1A receptors.

Complex signaling pathways may be involved in the actions of serotonergic psychedelics, including heteromeric complexes with metabotropic glutamate 2 receptor and additional signal transduction pathways.

Dysfunctional signaling of monoamines, including glutamate and 5-HT, is thought to play a major role in the etiology of depression. Ketamine and serotonergic psychedelics may act to restore the homeostasis required for proper dendritic function.

A drug may exert a gradient of excitatory and inhibitory effects on dendritic excitability across cells or brain regions, limiting the effects of the drug to a restricted dose range and safeguarding against high-intensity responses associated with drug toxicity.

Ketamine and serotonergic psychedelics act in various brain regions and may have off-target effects. Even within the frontal cortex, pyramidal neurons are embedded in cortical microcircuits, so considering the drugs’ actions at the individual cell level leads to an incomplete picture. Drug actions on other brain regions can regulate long-range synaptic inputs arriving at the dendrites, and dopaminergic terminals can play a crucial role.

Concluding Remarks

Ketamine and serotonergic psychedelics have sparked interest as potential ground-breaking neuropsychiatric therapies. Research is needed to clarify how these drugs work and how they can be used to treat patients.

Acknowledgments

This work was supported by the Yale Center for Psychedelic Science, NIH/NIMH grants R01MH112750 and R01MH121848, Simons Foundation Autism Research Initiative Pilot Award, and NIH/NIGMS Medical Scientist Training grant T32GM007205 (A.C.K.).