REDD1 is essential for stress-induced synaptic loss and depressive behavior
Open accessAbstract
Major depressive disorder (MDD) affects up to 17% of the population, causing profound personal suffering and economic loss. Clinical and preclinical studies have revealed that prolonged stress and MDD are associated with neuronal atrophy of cortical and limbic brain regions, but the molecular mechanisms underlying these morphological alterations have not yet been identified. Here, we show that stress increases levels of REDD1 (regulated in development and DNA damage responses-1), an inhibitor of mTORC1 (mammalian target of rapamycin complex-1; ref. 10), in rat prefrontal cortex (PFC). This is concurrent with a decrease in phosphorylation of signaling targets of mTORC1, which is implicated in protein synthesis-dependent synaptic plasticity. We also found that REDD1 levels are increased in the postmortem PFC of human subjects with MDD relative to matched controls. Mutant mice with a deletion of the gene encoding REDD1 are resilient to the behavioral, synaptic and mTORC1 signaling deficits caused by chronic unpredictable stress, whereas viral-mediated overexpression of REDD1 in rat PFC is sufficient to cause anxiety- and depressive-like behaviors and neuronal atrophy. Taken together, these postmortem and preclinical findings identify REDD1 as a critical mediator of the atrophy of neurons and depressive behavior caused by chronic stress exposure.
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Inhibition of mTORC1 decreases synapse formation in the PFC and is sufficient to cause depression-like behaviors in rodents in the absence of stress exposure, demonstrating a causal relationship between synapses and behavior.
“and inhibition of mTORC1 decreases synapse formation in the PFC and is sufficient to cause depression-like behaviors in rodents in the absence of stress exposure, demonstrating a causal relationship between synapses and behavior.”
From Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model (2020) · cites this paper as [28]
The paper’s AAV-REDD1 experiment (section labeled Abstract; no page available) reports that REDD1 overexpression in rat medial PFC inhibited mTORC1 signaling, reduced mature dendritic-spine density, and produced depressive-like behaviors. It supports the claim’s core finding in rats without reported stress exposure, but measured spine loss rather than decreased synapse formation and did not establish that the spine changes themselves caused the behaviors. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPostmortem PFC of human subjects with Major Depressive Disorder has reduced levels of BDNF, elevated levels of REDD1, and decreased levels of mTOR.
“postmortem PFC of human subjects with Major Depressive Disorder (MDD), similar to stressed rodents, have reduced levels of BDNF,168–173 elevated levels of REDD1,92 and decreased levels of mTOR.92,169”
From Chronic Stress Weakens Connectivity in the Prefrontal Cortex: Architectural and Molecular Changes. (2021) · cites this paper as [92]
In the postmortem dlPFC analysis (page unavailable), REDD1 mRNA was significantly elevated in the combined MDD cohorts. The paper reports only a nonsignificant trend toward lower mTOR mRNA (p = 0.098), so the unqualified claim of decreased mTOR levels overstates its finding. The BDNF clause is cited to other sources in the citing sentence, not to this paper. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSustained stress exposure induces loss of dendrites and spines in layer II/III pyramidal cells of rodent PFC and loss of the dendritic tufts of layer V pyramidal cells.
“Sustained stress exposure induces loss of dendrites and spines in layer II/III pyramidal cells of rodent PFC70–73 and loss of the dendritic tufts of layer V pyramidal cells74.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [74]
The paper reports that chronic unpredictable stress reduces spine synapses and spine density in the distal tufts of layer V pyramidal neurons in rodent medial PFC (passage [5], section labeled Abstract; page unavailable). It does not report loss of the dendritic tufts themselves. Citation 74 is attached to the layer V clause, so the separately cited layer II/III clause is not part of this verdict. (LLM, conf=0.85)
Experimental — accuracy not yet measuredmTor signaling increases spine generation in the apical tuft of layer V pyramidal cells in the rat PFC.
“Recent studies have shown that mTor (mammalian target of rapamycin) signaling increases spine generation in the apical tuft of layer V pyramidal cells in the rat PFC and that stress exposure inhibits this effect by increasing the expression of REDD1 (regulated in development and DNA damage responses 1) (Fig. 4, pink)74.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [74]
The paper states that rapid-acting antidepressants increase mTORC1 signaling and synaptogenesis in rat PFC, and reports that chronic stress raises REDD1 in rat PFC. It also reports stress-related spine loss in apical tufts of layer V neurons and protection in REDD1-knockout mice. It does not establish that increased mTOR signaling specifically generates spines in the apical tufts of rat layer V neurons, so the citing sentence combines findings at different levels of specificity. (LLM, conf=0.84)
Experimental — accuracy not yet measuredVirus-mediated overexpression of REDD1 in the rat PFC is sufficient to cause anxiety- and depressive-like behaviors and neuronal atrophy.
“Virus-mediated overexpression of REDD1 in the rat PFC is sufficient to cause anxiety- and depressive-like behaviors and neuronal atrophy. 199”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [199]
Repeated stress exposure decreases mTORC1 signaling, which is required for synapse formation and neuroplasticity.
“In addition, repeated stress exposure decreases mTORC1 signaling, which is required for synapse formation and neuroplasticity 28 ,”
From Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model (2020) · cites this paper as [28]
Increases in REDD1 have been found in the dlPFC of depressed patients, similar to what is seen in the stressed rat PFC.
“For example, increases in REDD1 have been found in the dlPFC of depressed patients, which is similar to what is seen in the stressed rat PFC74.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [74]
Stress exposure inhibits mTor-induced spine generation by increasing the expression of REDD1.
“Recent studies have shown that mTor (mammalian target of rapamycin) signaling increases spine generation in the apical tuft of layer V pyramidal cells in the rat PFC and that stress exposure inhibits this effect by increasing the expression of REDD1 (regulated in development and DNA damage responses 1) (Fig. 4, pink)74.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [74]
REDD1 shows elevated expression in PFC of animals exposed to chronic unpredictable stress and PFC of post-partum depressed humans.
“REDD1, an endogenous inhibitor of mTOR, shows the elevated expression in PFC of animals exposed to chronic unpredictable stress and PFC of post-partum depressed humans 114.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [114]
REDD1 knockdown renders animals more resilient to chronic stress-induced spine shrinkage and AMPAR current reduction.
“REDD1 knockdown renders animals to have greater resilience to the chronic stress-induced spine shrinkage and AMPAR current reduction 114.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [114]
The expression of REDD1, a negative regulator of mTORC1, is increased in PFC of depressed subjects.
“Postmortem studies demonstrated that the expression of REDD1, a negative regulator of mTORC1, is increased in PFC of depressed subjects30.”
From Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants (2016) · cites this paper as [30]
Chronic stress decreases mTORC1 signaling proteins; overexpression of REDD1 causes loss of synapses in the PFC; REDD1 deletion mutant mice are resilient to the synaptic and behavioral deficits caused by chronic stress.
“Rodent studies also demonstrated that chronic stress decreases mTORC1 signaling proteins30,54,55, that over expression of REDD1 causes loss of synapses in the PFC, and that REDD1 deletion mutant mice are resilient to the synaptic and behavioral deficits caused by chronic stress30”
From Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants (2016) · cites this paper as [30]
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“199 According to postmortem studies, the volume of the dlPFC is smaller and the density of neurons in the dlPFC is lower in MDD. 200 BDNF can modulate synaptic plasticity in the brain.”
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- Authors
- Ota, K. T., Liu, R.-J., Voleti, B., Maldonado-Aviles, J. G., Duric, V., Iwata, M., Dutheil, S., Duman, C., Boikess, S., Lewis, D. A., Stockmeier, C. A., DiLeone, R. J., Rex, C., Aghajanian, G. K., & Duman, R. S.
- Affiliations
- Yale University (US)
- Afraxis (United States) (US)
- University of Pittsburgh (US)
- University of Mississippi Medical Center (US)
- Corresponding author
- Duman, Ronald S
- ORCID
- Venue
- Nature Medicine
- Published
- 2014-04-13
- Volume
- 20
- Issue
- 5
- Pages
- 531-535
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4016190
- OpenAlex
- W2093932385
- Cited by
- 267
- References
- 33
- Citations by year
- 2026: 12 · 2025: 15 · 2024: 17 · 2023: 16 · 2022: 19 · 2021: 38 · 2020: 26 · 2019: 27 · 2018: 17 · 2017: 25 · 2016: 22 · 2015: 26 · 2014: 5
- FWCI
- 18.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000142)
- National Institute of Mental Health (R01MH093897, R37MH45481, F32MH98513, R37MH045481, R01MH93897, F32MH098513, R01MH105910)
- National Institute of General Medical Sciences (P30GM103328)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- REDD1, major depressive disorder, chronic stress, depression, synaptic loss, neuronal atrophy, mTORC1 signaling, prefrontal cortex, stress resilience, synaptic plasticity, protein synthesis, anxiety-like behavior, chronic unpredictable mild stress
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Animals, Anxiety Disorders, Major Depressive Disorder, Humans, Neurons, Synapses, Transcription Factors, Signal Transduction, Prefrontal Cortex, Multiprotein Complexes, Mice, Rats, TOR Serine-Threonine Kinases
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