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

Abstract

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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Figure 1: Chronic unpredictable stress increases REDD1 and decreases mTORC1 signaling in rat PFC.
Figure 2: REDD1 mRNA is increased in the dlPFC of patients with MDD.
Figure 3: REDD1-knockout mice are resilient to CUS-induced alterations in PFC.
Figure 4: REDD1 overexpression in rat mPFC increases depressive and anxiety-related behaviors and decreases mTORC1 signaling.

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Acknowledgements

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.

Author information

K.T.O. prepared the original draft of the manuscript and was involved in all aspects of the experimental design and research, including execution and analysis of all behavioral, biochemical and molecular experiments, rodent surgeries and dissections and design, construction and preparation of recombinant AAVs. R.-J.L. performed all electrophysiological recordings and neurobiotin spine density analyses. B.V. assisted with optimization and preparation of the recombinant AAVs and with rat surgeries. J.G.M.-A. and R.J.D. assisted in the design and construction of the overexpression construct. V.D. assisted with quantitative PCR execution and analysis. M.I. assisted with rodent behavioral testing and sample preparation. S.D. and C.D. assisted with sample preparation. S.B. and C.R. were responsible for ESP spine density imaging and analysis. D.A.L. and C.A.S. were responsible for human tissue generation and preparation of relevant human subjects' information. G.K.A. was involved in the analysis and interpretation of the electrophysiological and spine density experiments. R.S.D. was involved in all aspects of study design, data analysis, interpretation of results and preparation of the manuscript and figures. All authors discussed the results presented in the manuscript.

Correspondence to Ronald S Duman.

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Competing interests

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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