Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo
Neuron July 5, 2021 Ling-Xiao Shao, Clara Liao, Ian Gregg et al. 589 citations
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Neil K. Savalia
10 papers in the library · 818 citations · publishing 2020-2026
Papers
A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics
Trends in Neurosciences December 21, 2020 Neil K. Savalia, Ling-Xiao Shao, Alex C. Kwan 110 citations
Ketamine and serotonergic psychedelics like psilocybin both relieve depression and promote neural plasticity, despite targeting different molecular receptors. This opinion article proposes a conceptual framework suggesting their actions converge at the dendrites, where they both enhance and suppress membrane excitability. Mismatches in these opposing effects may explain differences in cell-type and region selectivity, the compounds' moderate range of effects and toxicity, and their plasticity-promoting capacities.
Psilocybin's lasting action requires pyramidal cell types and 5-HT2A receptors.
Nature June 1, 2025 Ling-Xiao Shao, Clara Liao, Pasha A. Davoudian et al. 75 citations
A single dose of psilocybin increases dendritic spine density in two types of pyramidal cells in the mouse medial frontal cortex: subcortical-projecting pyramidal tract (PT) and intratelencephalic (IT) neurons. Silencing PT neurons eliminates psilocybin's ability to reduce stress-related behaviors, while silencing IT neurons has no effect. Psilocybin boosts synaptic calcium transients and firing rates specifically in PT neurons shortly after administration. Knocking out the 5-HT2A receptor blocks psilocybin's effects on both stress-related behavior and structural plasticity. These findings identify PT neurons and the 5-HT2A receptor as essential for psilocybin's long-term actions.
Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo
bioRxiv (Cold Spring Harbor Laboratory) February 17, 2021 Ling-Xiao Shao, Clara Liao, Ian Gregg et al. 26 citations preprint
A single dose of psilocybin, a serotonergic psychedelic, caused a roughly 10% increase in the size and density of dendritic spines on layer 5 pyramidal neurons in the mouse medial frontal cortex. This structural remodeling began within 24 hours and persisted for at least one month, driven by an elevated rate of new spine formation. The drug also reduced stress-related behavioral deficits and increased excitatory neurotransmission. The findings demonstrate that psilocybin induces fast and enduring synaptic rewiring in the cortex, which may provide a structural basis for long-term integration of experiences and lasting therapeutic benefits.
Psilocybin triggers an activity-dependent rewiring of large-scale cortical networks
Cell December 5, 2025 Quan Jiang, Ling-Xiao Shao, Shenqin Yao et al. 15 citations
A single dose of psilocybin causes structural remodeling of dendritic spines in the medial frontal cortex of mice. Using monosynaptic rabies tracing, the researchers mapped brain-wide inputs to frontal cortical pyramidal neurons and found that psilocybin's effect on connectivity is network specific: it strengthens routing of inputs from perceptual and medial regions (homolog of the default mode network) to subcortical targets while weakening inputs that are part of cortico-cortical recurrent loops. The pattern of synaptic reorganization depends on drug-evoked spiking activity, as silencing a presynaptic region during psilocybin administration disrupts the rewiring. These results reveal how psilocybin impacts large-scale cortical network connectivity and show that neural activity modulation can sculpt psychedelic-evoked plasticity.
Single-nucleus transcriptomics reveals time-dependent and cell-type-specific effects of psilocybin on gene expression
bioRxiv (Cold Spring Harbor Laboratory) January 4, 2025 Clara Liao, Ethan O'Farrell, Yaman Qalieh et al. 3 citations preprint
A single dose of psilocybin triggers time-dependent and cell-type-specific changes in gene expression in the medial frontal cortex of mice. Excitatory neurons showed altered genes involved in synaptic plasticity, while GABAergic neurons showed changes in genes related to mitochondrial function and metabolism. These transcriptional responses occurred in an early phase at 1-2 hours and a late phase at 72 hours after administration. Ketamine produced similar transcriptional changes. These findings suggest that psilocybin's long-term neural and behavioral effects may stem from lasting alterations in gene expression.
Psychedelic drug action at dendrites is gated by behavioral state and serotonin receptors
bioRxiv (Cold Spring Harbor Laboratory) July 20, 2026 Neil K. Savalia, Ling-Xiao Shao, Cory A. Knox et al.
Psilocybin transiently increases calcium event rates in apical dendritic tufts of pyramidal tract neurons in the mouse medial frontal cortex, an effect that parallels the drug's brain pharmacokinetics. This acute effect occurs selectively during quiet wakefulness and depends on the 5-HT2A receptor. Under normal conditions, dendritic calcium signaling predicts subsequent spine formation, but psilocybin disrupts this relationship. The findings suggest that the mechanisms linking acute dendritic activity to long-term structural plasticity differ between physiological and psychedelic-induced plasticity.
Psilocybin reshapes cortical inhibition through selective interneuron recruitment.
bioRxiv : the preprint server for biology April 17, 2026 Pasha A. Davoudian, Quan Jiang, Cory A. Knox et al.
Psilocybin, a classic psychedelic, alters the activity of specific inhibitory neurons in the mouse medial frontal cortex. It reduces firing of somatostatin-expressing interneurons while increasing activity of parvalbumin-expressing interneurons. This cell type-specific response depends on the 5-HT1A receptor on somatostatin interneurons, and contributes to the drug's long-term behavioral effects. The findings reveal that psilocybin changes cortical inhibition in a targeted manner, highlighting a mechanism beyond the commonly studied pyramidal cells.
Pyramidal cell types and 5-HT 2A receptors are essential for psilocybin’s lasting drug action
bioRxiv (Cold Spring Harbor Laboratory) November 3, 2024 Ling-Xiao Shao, Clara Liao, Pasha A. Davoudian et al. preprint
A single dose of psilocybin increased the density of dendritic spines in both subcortical-projecting pyramidal tract (PT) and intratelencephalic (IT) cell types in the mouse medial frontal cortex. Silencing PT neurons eliminated psilocybin's ability to ameliorate stress-related phenotypes, whereas silencing IT neurons had no detectable effect. In PT neurons only, psilocybin boosted synaptic calcium transients and elevated firing rates acutely after administration. Targeted knockout of 5-HT2A receptors abolished psilocybin's effects on stress-related behavior and structural plasticity. These results identify a pyramidal cell type and the 5-HT2A receptor in the medial frontal cortex as essential for psilocybin's long-term drug action.
Visualizing drug actions on dendrites: psilocybin and other classic psychedelics
January 1, 2023 Ling-Xiao Shao, Clara Liao, Ian Gregg et al.
Psychedelics like psilocybin can alter neuronal structure in the frontal cortex. Using two-photon microscopy in mice, psilocybin administration led to changes in dendritic spines, the tiny protrusions on neurons that receive signals from other neurons. The effects were compared with those of other psychoactive drugs, suggesting that psychedelics may have unique impacts on brain cell architecture. These findings indicate a potential mechanism for how psychedelics could influence brain function and behavior.