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

• Published in: Nature medicine Vol. 20; no. 5; pp. 531 - 535
• Main Authors: Ota, Kristie T, Liu, Rong-Jian, Voleti, Bhavya, Maldonado-Aviles, Jaime G, Duric, Vanja, Iwata, Masaaki, Dutheil, Sophie, Duman, Catharine, Boikess, Steve, Lewis, David A, Stockmeier, Craig A, DiLeone, Ralph J, Rex, Christopher, Aghajanian, George K, Duman, Ronald S
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2014; Nature Publishing Group
• Subjects: 631/378/340; Analysis; Animals; Anxiety Disorders - etiology; Anxiety Disorders - genetics; Anxiety Disorders - pathology; Biomedicine; Cancer Research; Deoxyribonucleic acid; Depression, Mental; Depressive Disorder, Major - etiology; Depressive Disorder, Major - genetics; Depressive Disorder, Major - pathology; DNA; Economics; Humans; Infectious Diseases; letter; Mammals; Mechanistic Target of Rapamycin Complex 1; Mental depression; Metabolic Diseases; Mice; Molecular Medicine; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Neurons; Neurons - metabolism; Neurons - pathology; Neuropsychology; Neurosciences; Plasticity; Prefrontal Cortex - metabolism; Prefrontal Cortex - pathology; Protein synthesis; Psychopathology; Rats; Signal Transduction; Stress; Synapses; Synapses - genetics; Synapses - metabolism; Synapses - pathology; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.3513

Chronic stress can lead to depression. Ronald Duman and his colleagues show that REDD1 expression is increased in the brain of patients with major depressive disorder and is upregulated in the brains of stressed mice. Mice lacking REDD1 were resistant to stress-induced depressive behaviors, and unstressed rats in which REDD1 was artificially increased exhibited depressive behaviors. Major depressive disorder (MDD) affects up to 17% of the population, causing profound personal suffering and economic loss 1 . Clinical and preclinical studies have revealed that prolonged stress and MDD are associated with neuronal atrophy of cortical and limbic brain regions 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 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.