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

Lluis Miquel-Rio; Unai Sarriés-Serrano; María Sancho-Alonso; Eva Florensa-Zanuy; Verónica Paz; Esther Ruiz-Bronchal; Sharon Manashirov; Leticia Campa; Fuencisla Pilar-Cuéllar; Analia Bortolozzi

doi:10.1016/j.isci.2024.109787

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

iScience. 2024 Apr 18;27(5):109787. doi: 10.1016/j.isci.2024.109787. eCollection 2024 May 17.

Authors

Lluis Miquel-Rio^{1

2

3

4}, Unai Sarriés-Serrano^{1

2

3

5}, María Sancho-Alonso^{1

2

3}, Eva Florensa-Zanuy^{3

6}, Verónica Paz^{1

2

3}, Esther Ruiz-Bronchal^{1

2

3}, Sharon Manashirov^{1

3

7}, Leticia Campa^{1

2

3}, Fuencisla Pilar-Cuéllar^{3

6}, Analia Bortolozzi^{1

2

3}

Affiliations

¹ Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain.
² Systems Neuropharmacology Research Group, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain.
³ Biomedical Research Networking Center for Mental Health (CIBERSAM), Institute of Health Carlos III (ISCIII), 28029 Madrid, Spain.
⁴ University of Barcelona (UB), 08036 Barcelona, Spain.
⁵ University of the Basque Country UPV/EHU, E-48940 Leioa, Bizkaia, Spain.
⁶ Department of Molecular and Cellular Signaling, Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), University of Cantabria-CSIC, 39011 Santander, Spain.
⁷ miCure Therapeutics LTD., Tel-Aviv 6423902, Israel.

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.

Keywords: behavioral neuroscience; molecular biology; molecular neuroscience; neuroscience.