Format

Send to

Choose Destination
Neuron. 2018 Nov 7;100(3):551-563.e7. doi: 10.1016/j.neuron.2018.08.031. Epub 2018 Sep 13.

Menin Deficiency Leads to Depressive-like Behaviors in Mice by Modulating Astrocyte-Mediated Neuroinflammation.

Author information

1
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361102, P.R. China.
2
State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences and Peking Union Medical College, Neuroscience Center, Chinese Academy of Medical Sciences, Beijing 100005, P.R. China.
3
School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, P.R. China.
4
Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
5
Department of Basic Medical Science, Medical College, Xiamen University, Xiamen, Fujian 361102, P.R. China.
6
The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing 100850, P.R. China.
7
Institute of Mental Health Research at the Royal and Departments of Psychiatry and Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1Z7K4, Canada.
8
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361102, P.R. China; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
9
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361102, P.R. China; Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
10
State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences and Peking Union Medical College, Neuroscience Center, Chinese Academy of Medical Sciences, Beijing 100005, P.R. China. Electronic address: xuqi@pumc.edu.cn.
11
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361102, P.R. China. Electronic address: jiezhang@xmu.edu.cn.

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.

KEYWORDS:

IL-1β; NF-κB; astrocyte; chronic unpredictable mild stress; cytokine; depression; menin; neuroinflammation; p65; single nucleotide polymorphism

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center