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REDD1 is essential for stress-induced synaptic loss and depressive behavior
- Source :
- Nature Medicine. 20:531-535
- Publication Year :
- 2014
- Publisher :
- Springer Science and Business Media LLC, 2014.
-
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.
- Subjects :
- medicine.medical_specialty
Population
Prefrontal Cortex
mTORC1
Molecular neuroscience
Mechanistic Target of Rapamycin Complex 1
General Biochemistry, Genetics and Molecular Biology
Mice
03 medical and health sciences
0302 clinical medicine
Atrophy
Animals
Humans
Medicine
Chronic stress
Psychiatry
education
Prefrontal cortex
030304 developmental biology
Neurons
Depressive Disorder, Major
0303 health sciences
education.field_of_study
business.industry
TOR Serine-Threonine Kinases
General Medicine
medicine.disease
Anxiety Disorders
Rats
Multiprotein Complexes
Synapses
Synaptic plasticity
Major depressive disorder
business
Neuroscience
030217 neurology & neurosurgery
Signal Transduction
Transcription Factors
Subjects
Details
- ISSN :
- 1546170X and 10788956
- Volume :
- 20
- Database :
- OpenAIRE
- Journal :
- Nature Medicine
- Accession number :
- edsair.doi.dedup.....f77d83cc79d41dc0e290103c0d90a76f