title: 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 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.
authors.affiliation: Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Kristie T
authors.initials: KT
authors.lastname: Ota
authors.affiliation: Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Rong-Jian
authors.initials: RJ
authors.lastname: Liu
authors.affiliation: Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Bhavya
authors.initials: B
authors.lastname: Voleti
authors.affiliation: Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Jaime G
authors.initials: JG
authors.lastname: Maldonado-Aviles
authors.affiliation: 1] Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA. [2] Department of Physiology and Pharmacology, Des Moines University, Des Moines, Iowa, USA.
authors.forename: Vanja
authors.initials: V
authors.lastname: Duric
authors.affiliation: Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Iwata
authors.affiliation: Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Sophie
authors.initials: S
authors.lastname: Dutheil
authors.affiliation: Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Catharine
authors.initials: C
authors.lastname: Duman
authors.affiliation: Afraxis, La Jolla, California, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Boikess
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Lewis
authors.affiliation: Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, Mississippi, USA.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Stockmeier
authors.affiliation: Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DiLeone
authors.affiliation: Afraxis, La Jolla, California, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Rex
authors.affiliation: Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: George K
authors.initials: GK
authors.lastname: Aghajanian
authors.affiliation: Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Duman
mesh_terms: D000818:Animals; D001008:Anxiety Disorders / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D003865:Major Depressive Disorder / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D017397:Prefrontal Cortex / Q000378:metabolism / Q000473:pathology; D051381:Rats; D015398:Signal Transduction; D013569:Synapses / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: C469991:DDIT4 protein, human; D046912:Multiprotein Complexes; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
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