REDD1 is essential for stress-induced synaptic loss and depressive behavior : Nature Medicine : Nature Publishing Group
REDD1 is essential for stress-induced synaptic loss and depressive behavior : Nature Medicine : Nature Publishing Group
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.
