ER stress in mouse serotonin neurons triggers a depressive phenotype alleviated by ketamine targeting eIF2α signaling.

Depression involves disruptions in the endoplasmic reticulum (ER) of serotonin neurons. In mice, artificially inducing ER stress in these neurons reduced Egr1-dependent serotonin activity and neurotransmission, leading to impaired neuroplasticity in forebrain regions and depressive-like behaviors. Ketamine reversed these effects by activating eIF2α signaling, which rapidly restored neuroplasticity. The findings identify ER stress in serotonin neurons as a cellular mechanism in depression and highlight eIF2α as a key target for ketamine's fast antidepressant action.

Study at a glance

Abstract

Depression is a devastating mood disorder that causes significant disability worldwide. Current knowledge of its pathophysiology remains modest and clear biological markers are lacking. Emerging evidence from human and animal models reveals persistent alterations in endoplasmic reticulum (ER) homeostasis, suggesting that ER stress-related signaling pathways may be targets for prevention and treatment. However, the neurobiological basis linking the pathways involved in depression-related ER stress remains unknown. Here, we report that an induced model of ER stress in mouse serotonin (5-HT) neurons is associated with reduced Egr1-dependent 5-HT cellular activity and 5-HT neurotransmission, resulting in neuroplasticity deficits in forebrain regions and a depressive-like phenotype. Ketamine administration engages downstream eIF2α signaling to trigger rapid neuroplasticity events that rescue the depressive-like effects. Collectively, these data identify ER stress in 5-HT neurons as a cellular pathway involved in the pathophysiology of depression and show that eIF2α is critical in eliciting ketamine's fast antidepressant effects.