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

Area of Science:

• Neuroscience
• Molecular Biology
• Psychiatry

Background:

• Major depressive disorder (MDD) impacts 17% of the population, leading to significant suffering and economic burden.
• Prolonged stress and MDD are linked to neuronal atrophy in brain regions like the prefrontal cortex (PFC), but underlying molecular mechanisms remain unclear.

Purpose of the Study:

• To identify the molecular mechanisms linking stress, MDD, and neuronal atrophy.
• To investigate the role of REDD1 (regulated in development and DNA damage responses-1) in stress-induced brain changes and depressive behaviors.

Main Methods:

• Measured REDD1 levels and mTORC1 (mammalian target of rapamycin complex-1) signaling in rat prefrontal cortex (PFC) following stress exposure.
• Analyzed postmortem PFC tissue from human subjects with MDD and control groups.
• Utilized genetically modified mice lacking REDD1 and viral vectors for REDD1 overexpression in rats to assess behavioral and synaptic outcomes.

Main Results:

• Stress significantly increased REDD1 levels and decreased mTORC1 signaling in rat PFC.
• Elevated REDD1 levels were observed in the postmortem PFC of individuals with MDD.
• Mice lacking REDD1 were resilient to stress-induced behavioral and synaptic deficits.
• Overexpression of REDD1 in rats induced anxiety- and depressive-like behaviors and neuronal atrophy.

Conclusions:

• REDD1 is a critical mediator of neuronal atrophy and depressive behavior induced by chronic stress.
• Targeting REDD1 may offer a novel therapeutic strategy for MDD and stress-related disorders.