Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
Won Chan Oh
Max Planck Florida Institute for Neuroscience, Jupiter, United States
Brian S Muntean
Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
Keqiang Xie
Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
Alice Filippini
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
Xiangyang Xie
Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
Rachel Satterfield
Max Planck Florida Institute for Neuroscience, Jupiter, United States
Jazmine D W Yaeger
Center for Brain and Behavior Research, University of South Dakota, Vermillion, United States; Department of Biology, University of South Dakota, Vermillion, United States
Kenneth J Renner
Center for Brain and Behavior Research, University of South Dakota, Vermillion, United States; Department of Biology, University of South Dakota, Vermillion, United States
Max Planck Florida Institute for Neuroscience, Jupiter, United States; Department of Anatomy and Cell Biology, University of Iowa, Iowa, United States; Aging Mind and Brain Initiative, University of Iowa, Iowa, United States; Department of Otolaryngology, Carver College of Medicine, University of Iowa, Iowa, United States
Baoji Xu
Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
Hyungbae Kwon
Max Planck Florida Institute for Neuroscience, Jupiter, United States; Max Planck Institute of Neurobiology, Martinsried, Germany
Stress can be a motivational force for decisive action and adapting to novel environment; whereas, exposure to chronic stress contributes to the development of depression and anxiety. However, the molecular mechanisms underlying stress-responsive behaviors are not fully understood. Here, we identified the orphan receptor GPR158 as a novel regulator operating in the prefrontal cortex (PFC) that links chronic stress to depression. GPR158 is highly upregulated in the PFC of human subjects with major depressive disorder. Exposure of mice to chronic stress also increased GPR158 protein levels in the PFC in a glucocorticoid-dependent manner. Viral overexpression of GPR158 in the PFC induced depressive-like behaviors. In contrast GPR158 ablation, led to a prominent antidepressant-like phenotype and stress resiliency. We found that GPR158 exerts its effects via modulating synaptic strength altering AMPA receptor activity. Taken together, our findings identify a new player in mood regulation and introduce a pharmacological target for managing depression.
