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Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation
Open accessAbstract
Why is ketamine an antidepressant?: A better understanding of the mechanisms underlying the action of antidepressants is urgently needed. Moda-Sava et al. explored a possible mode of action for the drug ketamine, which has recently been shown to help patients recover from depression (see the Perspective by Beyeler). Ketamine rescued behavior in mice that was associated with depression-like phenotypes by selectively reversing stress-induced spine loss and restoring coordinated multicellular ensemble activity in prefrontal microcircuits. The initial induction of ketamine's antidepressant effect on mouse behavior occurred independently of effects on spine formation. Instead, synaptogenesis in the prefrontal region played a critical role in nourishing these effects over time. Interventions aimed at enhancing the survival of restored synapses may thus be useful for sustaining the behavioral effects of fast-acting antidepressants. Science , this issue p. eaat8078 ; see also p. 129
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In the citing paper
“Activation of AS-PaRac1 three hours post-treatment did not impact tail suspension test behavior 48 hours post-treatment, which is prior to the onset of spine formation by ketamine 12 hours post-treatment.”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Moda-Sava et al., 2019
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Using a chronic (21 day) corticosterone (CORT) exposure model of depression in mice, this study demonstrated that CORT induces dendritic spine elimination in the mPFC which is rescued 24 hours following a single ketamine treatment (10 mg/kg i.p.).”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Moda-Sava et al., 2019
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The rapidity and magnitude of ketamine's effects have been attributed to its ability to rapidly reverse neuroplasticity deficits in animal models 3,4,10,34 .”
From Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model (2020) · cites this paper as [10]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Impairments of neuroplasticity often characterize disorders of negative affect including depression 3,4 and multiple efficacious therapies often reverse such deficits 10,148-151 .”
From Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model (2020) · cites this paper as [10]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Ketamine and psychedelics modulate cortical neuron function by increasing dendritic spine and synapse density in the PFC (129, 146–149)”
From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [129]
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“While animal studies show that ketamine-induced increases in synaptic proteins and density 14 67 40”
From Imaging the effect of ketamine on synaptic density (SV2A) in the living brain (2022) · cites this paper as [40]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Chronic exposure to uncontrollable stress causes loss of spines and dendrites in the prefrontal cortex (PFC), a recently evolved brain region that provides top-down regulation of thought, action, and emotion.”
From Chronic Stress Weakens Connectivity in the Prefrontal Cortex: Architectural and Molecular Changes. (2021) · cites this paper as [77]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“ketamine rescued the increase in immobility produced by CORT exposure during the tail suspension test starting at three hours to one-week post-treatment.”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Moda-Sava et al., 2019
The cited source says what the claim attributes to it.
In the citing paper
“specific deletion of the newly formed spines 24 hours post-treatment via activated synapse-targeting photoactivatable Rac1 (AS-PaRac1), which collapses newly formed spines through light stimulation, reversed the effects of ketamine in the tail suspension test 48 hours post-treatment.”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Moda-Sava et al., 2019
The cited source says what the claim attributes to it.
In the citing paper
“Ketamine restored dendritic spines that were specifically lost during the CORT exposure.”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Moda-Sava et al., 2019
The cited source says what the claim attributes to it.
In the citing paper
“An elegant recent study provided further evidence that new synapse formation is causally related to the antidepressant actions of ketamine 10 .”
From Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model (2020) · cites this paper as [10]
The cited source says what the claim attributes to it.
In the citing paper
“As an example, we discuss the potential for ketamine-which exhibits both rapid plasticity-enhancing effects in animal models 4,10 and rapid clinical effects in human patients 11,12 -to provide a test of the predictions of this integrative model, including simultaneous and correlated reversals of multiple plasticity-related deficits across levels of analysis.”
From Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model (2020) · cites this paper as [10]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“These structural changes are accompanied by depressive phenotypes related to motivation (129), anxiety (122), and anhedonia (122, 129).”
From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [129]
The cited source says what the claim attributes to it.
In the citing paper
“Liston et al. recently used a photoactivatable Rac1 to demonstrate that ketamine-induced spine growth in the PFC was causally related to long-lasting antidepressant effects of the drug in rodents (129).”
From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [129]
The cited source says what the claim attributes to it.
In the citing paper
“In both humans and rodents, the antidepressant responses of ketamine appear to last for about 1 week.”
From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [129]
The cited source says what the claim attributes to it.
In the citing paper
“Indeed, recent in vivo work indicates that ketamine regrows the dendritic spines lost to stress in a targeted manner.”
From Imaging the effect of ketamine on synaptic density (SV2A) in the living brain (2022) · cites this paper as [40]
The cited source says what the claim attributes to it.
In the citing paper
“With chronic stress exposure, there is architectural loss of mPFC spines and dendrites (Moda-Sava et al., 2019, Radley et al., 2006) that correlates with impaired PFC cognitive functioning (Hains et al., 2009, Hains et al., 2015, Liston et al., 2006).”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Moda-Sava et al., 2019
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Computational tools that integrate fMRI and EEG already recover predictive signatures of response and can propose dose and timing schedules aligned to individual network states [14,37,181].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [181]
Experimental — accuracy not yet measuredIn the citing paper
“Similarly to observation in MDD, CORT mice showed spine loss in prefrontal microcircuit and altered neuronal brain-derived neurotrophic factor (BDNF) signaling and neurogenesis with a reduced progenitor cell proliferation in hippocampal and cortical structures.6,7”
From Synaptic Vesicle 2A (SV2A) Positron Emission Tomography (PET) Imaging as a Marker of Therapeutic Response in a Mouse Model of Depression (2025) · cites this paper as [7]
In the citing paper
“Second, another study demonstrated that the induction of antidepressant behavioral effects occurs in vivo independently of (and before) actual spine formation. However, glutamate-induced synaptogenesis in their study played a critical role in sustaining the effects over the subsequent week [80].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [80]
In the citing paper
“Multiple studies have reported similar occurrences with ketamine increasing dendritic spine density within 12–24 h of administration (Li et al., 2010; Liu et al., 2013; Moda-Sava et al., 2019).”
From A single subanaesthetic dose of the rapid-acting antidepressant S-ketamine raises presynaptic SV2A density in limbic regions of the Wistar Kyoto rat model of depression (2024) · cites this paper as Moda-Sava et al., 2019
In the citing paper
“Moda-Sava, et al. [145] used longitudinal imaging to demonstrate that the induction of depression-related behavior by chronic stress in mice, simulated by chronic corticosterone (CORT) exposure, correlated with targeted dendritic spine elimination within prefrontal cortex micro-circuits.”
From Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression (2025) · cites this paper as [145]
In the citing paper
“while these studies found that ketamine treatment selectively restored spines eliminated during CORT exposure”
From Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression (2025) · cites this paper as [145]
In the citing paper
“suggesting that spinogenesis may be important for the long-term maintenance of these behavioral effects”
From Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression (2025) · cites this paper as [145]
In the citing paper
“the authors observed a relationship between the degree to which ketamine was able to restore spines eliminated during CORT exposure and the sustained (2 days -1 week) antidepressant response”
From Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression (2025) · cites this paper as [145]
In the citing paper
“the effect of ketamine on antidepressant behavior preceded its effects on spine formation”
From Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression (2025) · cites this paper as [145]
In the citing paper
“suggesting spinogenesis is not required for inducing ketamine's effects on behavior”
From Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression (2025) · cites this paper as [145]
In the citing paper
“Ketamine and other fast-acting antidepressant candidates all produce a rapid restoration of dendritic spine density in the PFC in stressed and unstressed animals with the same rapid time course as its behavioral actions [145, 187, 202, 203], implying the restoration of synaptic and circuit function, too.”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [145]
In the citing paper
“Ketamine and other fast-acting antidepressant candidates all produce a rapid restoration of dendritic spine density in the PFC in stressed and unstressed animals with the same rapid time course as its behavioral actions [145, 187, 202, 203], implying the restoration of synaptic and circuit function, too.”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [145]
In the citing paper
“Ketamine and other fast-acting antidepressant candidates all produce a rapid restoration of dendritic spine density in the PFC in stressed and unstressed animals with the same rapid time course as its behavioral actions [145, 187, 202, 203], implying the restoration of synaptic and circuit function, too.”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [145]
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Citations
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Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., & Krystal, J. H. (2000) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00230-9 · Cited by 3,856
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mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists
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“An elegant recent study provided further evidence that new synapse formation is causally related to the antidepressant actions of ketamine [10].”
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Metadata
- Authors
- Moda-Sava, R. N., Murdock, M. H., Parekh, P. K., Fetcho, R. N., Huang, B. S., Huynh, T. N., Witztum, J., Shaver, D. C., Rosenthal, D. L., Alway, E. J., Lopez, K., Meng, Y., Nellissen, L., Grosenick, L., Milner, T. A., Deisseroth, K., Bito, H., Kasai, H., & Liston, C.
- Affiliations
- Weill Cornell Medicine (US)
- Stanford University (US)
- The University of Tokyo (JP)
- Center for Disease Biology and Integrative Medicine, The University of Tokyo (JP)
- Corresponding author
- Moda-Sava, R. N.
- Murdock, M. H.
- Parekh, P. K.
- Liston, C.
- ORCID
- Venue
- Science
- Published
- 2019-04-12
- Volume
- 364
- Issue
- 6436
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC6785189
- OpenAlex
- W2935995671
- Cited by
- 643
- References
- 96
- Citations by year
- 2026: 64 · 2025: 92 · 2024: 91 · 2023: 91 · 2022: 91 · 2021: 96 · 2020: 84 · 2019: 34
- FWCI
- 47.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Science Foundation
- National Institute of Mental Health (R00 MH097822, R01 MH109685)
- Simons Foundation (429965)
- Whitehall Foundation
- Rita Allen Foundation
- KAKENHI (Grant 17H06312)
- Japan Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science, and Technology
- Hartwell Foundation
- One Mind Institute
- Klingenstein-Simons Fellowship in Brain Science
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- depression, antidepressant effects, ketamine, dendritic spine formation, medial prefrontal cortex, postsynaptic neurons
- MeSH terms
- Animals, Antidepressive Agents, Corticosterone, Depressive Disorder, Disease Models, Animal, Escape Reaction, Ketamine, Mice, Inbred C57BL, Mice, Transgenic, Neuronal Plasticity, Stress, Psychological, Synapses, Prefrontal Cortex, Dendritic Spines, Mice
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