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

Nat Med. 2014 May;20(5):531-5. doi: 10.1038/nm.3513. Epub 2014 Apr 13.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety Disorders / etiology
  • Anxiety Disorders / genetics*
  • Anxiety Disorders / pathology
  • Depressive Disorder, Major / etiology
  • Depressive Disorder, Major / genetics*
  • Depressive Disorder, Major / pathology
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Neurons / metabolism
  • Neurons / pathology
  • Prefrontal Cortex / metabolism
  • Prefrontal Cortex / pathology
  • Rats
  • Signal Transduction
  • Synapses / genetics
  • Synapses / metabolism
  • Synapses / pathology*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism

Substances

  • DDIT4 protein, human
  • Multiprotein Complexes
  • Transcription Factors
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases