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

Lige Leng, Kai Zhuang, Zeyue Liu, Changquan Huang, Yuehong Gao, Guimiao Chen, Hui Lin, Yu Hu, Di Wu, Meng Shi, Wenting Xie, Hao Sun, Zhicheng Shao, Huifang Li, Kunkun Zhang, Wei Mo, Timothy Y. Huang, Maoqiang Xue, Zengqiang Yuan, Xia ZhangGuojun Bu, Huaxi Xu, Qi Xu, Jie Zhang

Research output: Contribution to journalArticle

21 Scopus citations

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. Mechanisms underlying astrocyte-mediated neuroinflammation in depression remain unclear. Menin regulates NF-κB activity in astrocytes to promote neuroinflammation. Clinically, a MEN1 SNP is associated with the onset of depression. This study reveals a distinct role for menin in neuroinflammation and depression.

Original languageEnglish (US)
Pages (from-to)551-563.e7
JournalNeuron
Volume100
Issue number3
DOIs
StatePublished - Nov 7 2018

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

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  • Cite this

    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, T. Y., Xue, M., Yuan, Z., ... Zhang, J. (2018). Menin Deficiency Leads to Depressive-like Behaviors in Mice by Modulating Astrocyte-Mediated Neuroinflammation. Neuron, 100(3), 551-563.e7. https://doi.org/10.1016/j.neuron.2018.08.031