1. Menin Deficiency Leads to Depressive-like Behaviors in Mice by Modulating Astrocyte-Mediated Neuroinflammation.
- Author
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Leng L, Zhuang K, Liu Z, Huang C, Gao Y, Chen G, Lin H, Hu Y, Wu D, Shi M, Xie W, Sun H, Shao Z, Li H, Zhang K, Mo W, Huang TY, Xue M, Yuan Z, Zhang X, Bu G, Xu H, Xu Q, and Zhang J
- Subjects
- Adult, Animals, Astrocytes pathology, Cells, Cultured, Depressive Disorder, Major genetics, Depressive Disorder, Major psychology, Female, Humans, Inflammation genetics, Inflammation metabolism, Inflammation psychology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Middle Aged, Proto-Oncogene Proteins genetics, Stress, Psychological genetics, Stress, Psychological psychology, Astrocytes metabolism, Depressive Disorder, Major metabolism, Proto-Oncogene Proteins deficiency, Stress, Psychological metabolism
- Abstract
Astrocyte dysfunction and inflammation are associated with the pathogenesis of major depressive disorder (MDD). However, the mechanisms underlying these effects remain largely unknown. Here, we found that multiple endocrine neoplasia type 1 (Men1; protein: menin) expression is attenuated in the brain of mice exposed to CUMS (chronic unpredictable mild stress) or lipopolysaccharide. Astrocyte-specific reduction of Men1 (GcKO) led to depressive-like behaviors in mice. We observed enhanced NF-κB activation and IL-1β production with menin deficiency in astrocytes, where depressive-like behaviors in GcKO mice were restored by NF-κB inhibitor or IL-1β receptor antagonist. Importantly, we identified a SNP, rs375804228, in human MEN1, where G503D substitution is associated with a higher risk of MDD onset. G503D substitution abolished menin-p65 interactions, thereby enhancing NF-κB activation and IL-1β production. Our results reveal a distinct astroglial role for menin in regulating neuroinflammation in depression, indicating that menin may be an attractive therapeutic target in MDD., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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