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REDD1 is essential for stress-induced synaptic loss and depressive behavior.

Ota KT, Liu RJ, Voleti B, Maldonado-Aviles JG, Duric V, Iwata M, Dutheil S, Duman C, Boikess S, Lewis DA, Stockmeier CA, DiLeone RJ, Rex C, Aghajanian GK, Duman RS - Nat. Med. (2014)

Bottom Line: Major depressive disorder (MDD) affects up to 17% of the population, causing profound personal suffering and economic loss.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.

ABSTRACT
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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REDD1 mRNA is increased in the dlPFC of MDD patients(a) Results are the mean ± SEM fold change relative to control of REDD1 mRNA in dlPFC of MDD subjects or psychiatrically-healthy controls (Control n=36; MDD n=36). (b) Results are the mean ± SEM fold change relative to control of mTOR mRNA in dlPFC of MDD subjects or psychiatrically-healthy controls (Control n=35; MDD n=37). White data points indicate subjects from cohort 1; green data points indicate subjects from cohort 2. Target mRNA levels have been normalized to GAPDH mRNA. (*) p < 0.05 control vs. MDD.
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Figure 2: REDD1 mRNA is increased in the dlPFC of MDD patients(a) Results are the mean ± SEM fold change relative to control of REDD1 mRNA in dlPFC of MDD subjects or psychiatrically-healthy controls (Control n=36; MDD n=36). (b) Results are the mean ± SEM fold change relative to control of mTOR mRNA in dlPFC of MDD subjects or psychiatrically-healthy controls (Control n=35; MDD n=37). White data points indicate subjects from cohort 1; green data points indicate subjects from cohort 2. Target mRNA levels have been normalized to GAPDH mRNA. (*) p < 0.05 control vs. MDD.

Mentions: To assess the relevance of REDD1 to MDD, we analyzed REDD1 expression in postmortem dorsolateral PFC (dlPFC) of two separate cohorts of depressed subjects. In the first cohort, there was a 1.22-fold increase of REDD1 mRNA in the dlPFC of MDD subjects relative to controls (p = 0.18). This effect was corroborated in the second cohort, where there was a significant 2.57-fold increase (p = 0.025). Combined analysis of the two cohorts revealed a significant overall 1.60-fold increase of REDD1 in MDD patients relative to psychiatrically healthy controls (p = 0.012) (Fig. 2a). There was also a trend for decreased levels of mTOR mRNA in the combined samples (p = 0.098) (Fig. 2b). ANCOVA revealed that neither sex nor medication status was a significant covariate for REDD1 or mTOR expression. Sustained activation of the HPA axis, consistently observed in MDD patients (18), could underlie this observed increase of REDD1.


REDD1 is essential for stress-induced synaptic loss and depressive behavior.

Ota KT, Liu RJ, Voleti B, Maldonado-Aviles JG, Duric V, Iwata M, Dutheil S, Duman C, Boikess S, Lewis DA, Stockmeier CA, DiLeone RJ, Rex C, Aghajanian GK, Duman RS - Nat. Med. (2014)

REDD1 mRNA is increased in the dlPFC of MDD patients(a) Results are the mean ± SEM fold change relative to control of REDD1 mRNA in dlPFC of MDD subjects or psychiatrically-healthy controls (Control n=36; MDD n=36). (b) Results are the mean ± SEM fold change relative to control of mTOR mRNA in dlPFC of MDD subjects or psychiatrically-healthy controls (Control n=35; MDD n=37). White data points indicate subjects from cohort 1; green data points indicate subjects from cohort 2. Target mRNA levels have been normalized to GAPDH mRNA. (*) p < 0.05 control vs. MDD.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4016190&req=5

Figure 2: REDD1 mRNA is increased in the dlPFC of MDD patients(a) Results are the mean ± SEM fold change relative to control of REDD1 mRNA in dlPFC of MDD subjects or psychiatrically-healthy controls (Control n=36; MDD n=36). (b) Results are the mean ± SEM fold change relative to control of mTOR mRNA in dlPFC of MDD subjects or psychiatrically-healthy controls (Control n=35; MDD n=37). White data points indicate subjects from cohort 1; green data points indicate subjects from cohort 2. Target mRNA levels have been normalized to GAPDH mRNA. (*) p < 0.05 control vs. MDD.
Mentions: To assess the relevance of REDD1 to MDD, we analyzed REDD1 expression in postmortem dorsolateral PFC (dlPFC) of two separate cohorts of depressed subjects. In the first cohort, there was a 1.22-fold increase of REDD1 mRNA in the dlPFC of MDD subjects relative to controls (p = 0.18). This effect was corroborated in the second cohort, where there was a significant 2.57-fold increase (p = 0.025). Combined analysis of the two cohorts revealed a significant overall 1.60-fold increase of REDD1 in MDD patients relative to psychiatrically healthy controls (p = 0.012) (Fig. 2a). There was also a trend for decreased levels of mTOR mRNA in the combined samples (p = 0.098) (Fig. 2b). ANCOVA revealed that neither sex nor medication status was a significant covariate for REDD1 or mTOR expression. Sustained activation of the HPA axis, consistently observed in MDD patients (18), could underlie this observed increase of REDD1.

Bottom Line: Major depressive disorder (MDD) affects up to 17% of the population, causing profound personal suffering and economic loss.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus