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

Neuron
Lige LengJie Zhang

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.

Citations

Aug 3, 2019·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Arnaud TantiNaguib Mechawar
Feb 20, 2020·The Journal of Comparative Neurology·Attilio IemoloFrancesca Telese
Feb 15, 2019·International Journal of Molecular Sciences·Zhiwen ZhouRyuta Koyama
Feb 6, 2019·Frontiers in Neurology·Anelia A Y KassiShyam Gajavelli
Aug 6, 2019·Frontiers in Psychiatry·Luca SteardoPasquale De Fazio
Oct 11, 2020·Biomedicines·Jacopo Meldolesi
Oct 18, 2020·Science China. Life Sciences·Xiaoning JiaHailan Hu
Nov 17, 2020·Frontiers in Cell and Developmental Biology·Tianyu ZouCheng Mei
Aug 10, 2020·Neuroscience and Biobehavioral Reviews·Marcus Augusto-OliveiraMaria Elena Crespo-Lopez
Dec 9, 2020·Journal of Affective Disorders·Weibin HuangJing Zhang
Nov 5, 2020·Molecular Psychiatry·Butian ZhouXiaoping Tong
May 29, 2020·Neuropharmacology·Matjaž StenovecRobert Zorec
May 22, 2021·Journal of Neuroendocrinology·Savani Anbalagan
Oct 13, 2021·Cellular and Molecular Neurobiology·Shusheng WuLongfei Du
Nov 24, 2021·Frontiers of Medicine·Yang LiaoZengqiang Yuan

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