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Título: | Antidepressant actions of ketamine engage cellular mechanisms of endoplasmic reticulum stress by the eIF2¿ pathway |
Autor: | Miquel-Rio, Lluís CSIC ORCID; Sarries-Serrano, Unai; Paz, Verónica CSIC ORCID; Campa, Leticia CSIC ORCID; Bortolozzi, Analía CSIC ORCID | Fecha de publicación: | 9-jul-2022 | Citación: | FENS (2022) | Resumen: | Aims: Depression is a devastating mood disorder that causes profound disability worldwide. Despite the growing number of antidepressant medications available, treatment options for depression are limited. Therefore, it is imperative to understand the etiology and pathophysiology of depression to discover novel therapeutic targets of action. Here, we explore how endoplasmic reticulum (ER) stress might play an important role in the pathophysiology of depression and how the antidepressant ketamine actions involve ER pathways Methods: We generated a mouse model of ER stress in serotonin (5-HT) neurons using the stressor tunicamycin (200 μg/μl). We examined ER/UPR pathway markers by Western blot, neuroplasticity gene expression (BDNF, TrkB, VEGF, Neuritin, PSD95, and Zif268) by in situ hybridization, 5-HT release by microdialysis, and behavioral depressive-like phenotype. Ketamine (10 mg/kg, i.p.) was used to reverse the ER stress-induced depressive mouse model. Results: Tunicamycin-induced ER stress in 5-HT neurons left a time-dependent increase in GRP78 and CHOP protein levels. In addition, increased phosphorylation of eIF2α and eEF2 was found, suggesting activation of PERK pathway. Tunicamycin-treated mice exhibited an anxious/depressive phenotype, reduced 5-HT release in the medial prefrontal cortex, and changes in neuroplasticity gene expression in 5-HT projection areas. A single dose of ketamine reversed the depressive phenotype 30 minutes later, which is associated with reduced levels of phosphorylated eIF2α and recovery of BDNF expression. Conclusions: The results strongly indicate that ER stress and UPR may represent cellular pathogenic mechanisms in the development of mood disorders and that eIF2α pathway is central for the antidepressant activity of ketamine. | Descripción: | Trabajo presentado en FENS 2022, celebrado en París (Francia), del 9 al 13 de julio de 2022 | URI: | http://hdl.handle.net/10261/284279 |
Aparece en las colecciones: | (IIBB) Comunicaciones congresos |
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