Stress and autophagy

Abstract

Stress disrupts homeostasis, and although various processes in the brain quickly restore equilibrium following acute stress, this is not the case during chronic stress, which can lead to depression. A paper published in Nature identifies autophagy as an important player in this phenomenon. The authors found that chronic stress in male mice downregulated autophagy in neurons in the lateral habenula (LHb) by increasing mTOR signaling. By contrast, acute stress increased autophagy in this area by increasing AMPK activation. Depression-like behavior in chronically stressed mice could be reversed or prevented by pharmacological activation of autophagy in the LHb. Various antidepressant drugs, including an mTOR inhibitor, required autophagy in this area to do their job. Autophagy mainly targeted postsynaptic glutamate receptors (GluRs) for degradation, and reduced autophagy — such as that in chronically stressed mice — was associated with excessive GluR expression and caused LHb neuron hyperactivity, impaired synaptic long-term depression, and depression-like behavior. Together, these findings show that autophagy is important for maintaining homeostasis in the LHb by counterbalancing the excessive GluRs upregulated by stress, and they suggest that restoring autophagy, possibly with an mTOR inhibitor, may be a promising target for antidepressant research.

Original reference: Nature https://www.nature.com/articles/s41586-025-08807-4 (2025)