Major depressive disorder (MDD) affects up to 17% of the population, causing profound personal suffering and economic loss1. Clinical and preclinical studies have revealed that prolonged stress and MDD are associated with neuronal atrophy of cortical and limbic brain regions2,3,4,5,6,7,8,9, 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.
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This work is supported by US National Institutes of Health NIMH R37MH45481 (R.S.D.), NIMH R01MH93897 (R.S.D.), NIMH F32MH98513 (K.T.O.) and NIGMS P30GM103328 (C.A.S.), the State of Connecticut and Yale University. We thank the families consenting to donate brain tissue and be interviewed for the human tissue samples and the Cuyahoga County Medical Examiner's Office for assistance. We thank G. Rajkowska for identification of anatomically comparable regions of dlPFC. We thank Quark Pharmaceuticals for providing the REDD1 plasmid and REDD1-knockout mice. We thank M. Banasr for helpful discussions on behavioral experiments, X.-Y. Li for assistance in breeding and genotyping REDD1-knockout mice, and A. Lepack, W. Andres and Z. LaPalombara for technical assistance. We thank J. Taylor, M. Picciotto and A. Nairn for critical reading of the manuscript.
D.A.L. currently receives investigator-initiated research support from Bristol-Myers Squibb and Pfizer and from 2012–2014 served as a consultant in the areas of target identification and validation and new compound development to Autifony, Bristol-Myers Squibb, Concert Pharmaceuticals and Sunovion.
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Ota, K., Liu, R., Voleti, B. et al. REDD1 is essential for stress-induced synaptic loss and depressive behavior. Nat Med 20, 531–535 (2014) doi:10.1038/nm.3513
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