ER stress in mouse serotonin neurons triggers a depressive phenotype alleviated by ketamine targeting eIF2α signaling.
iScience – May 17, 2024
Source: PubMed
Summary
Stress in brain cells that produce serotonin can trigger depression-like behavior in mice. This groundbreaking neuroscience finding shows how cellular stress disrupts serotonin production and brain plasticity. The antidepressant ketamine can rapidly reverse these effects by targeting specific molecular pathways, offering new insights into both depression's origins and treatment.
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.