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

• Published in: iScience Vol. 27; no. 5; p. 109787
• Main Authors: Miquel-Rio, Lluis, Sarriés-Serrano, Unai, Sancho-Alonso, María, Florensa-Zanuy, Eva, Paz, Verónica, Ruiz-Bronchal, Esther, Manashirov, Sharon, Campa, Leticia, Pilar-Cuéllar, Fuencisla, Bortolozzi, Analia
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.05.2024; Elsevier
• Subjects: behavioral neuroscience; molecular biology; molecular neuroscience; neuroscience; molecular biology; behavioral neuroscience; molecular neuroscience; neuroscience
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2024.109787

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. [Display omitted] •ER stress on raphe 5-HT neurons triggers a depressive-like phenotype in mice•Altered eIF2α pathway in 5-HT neurons induces global changes in brain neuroplasticity•EIF2α signaling is critical in eliciting the rapid antidepressant effects of ketamine Molecular biology; Neuroscience; Behavioral neuroscience; Molecular neuroscience