REDD1 is essential for stress-induced synaptic loss and depressive behavior
Autor: | Steven Ray Boikess, Craig A. Stockmeier, David A. Lewis, Ralph J. DiLeone, Vanja Duric, Bhavya Voleti, Kristie T. Ota, Rong-Jian Liu, Sophie Dutheil, Jaime G. Maldonado-Avilés, Masaaki Iwata, George K. Aghajanian, Ronald S. Duman, Christopher S. Rex, Catharine H. Duman |
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Rok vydání: | 2014 |
Předmět: |
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 |
Zdroj: | Nature Medicine. 20:531-535 |
ISSN: | 1546-170X 1078-8956 |
Popis: | 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. |
Databáze: | OpenAIRE |
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