Manganese exposure leads to depressive-like behavior through disruption of the Gln–Glu–GABA metabolic cycle,Journal of Hazardous Materials

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Manganese exposure leads to depressive-like behavior through disruption of the Gln–Glu–GABA metabolic cycle
Journal of Hazardous Materials ( IF 12.2 ) Pub Date : 2024-09-10 , DOI: 10.1016/j.jhazmat.2024.135808
Yujie Bi ₁ , Nannan Huang ₁ , Duo Xu ₁ , Shenshen Wu ₂ , Qingtao Meng ₂ , Hanqing Chen ₁ , Xiaobo Li ₂ , Rui Chen ₃

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There is a correlation between long-term manganese (Mn) exposure and the Parkinson's-like disease (PD), with depression as an early symptom of PD. However, the direct relationship between Mn exposure and depression, and the mechanisms involved, remain unclear. We found that Mn exposure led to depressive-like behavior and mild cognitive impairment in mice, with Mn primarily accumulating in the cornu ammonis 3 (CA3) area of the hippocampus. Mice displayed a reduction in neuronal dendritic spines and damage to astrocytes specifically in the CA3 area. Spatial metabolomics revealed that Mn downregulated glutamic acid decarboxylase 1 (GAD1) expression in astrocytes, disrupting the Glutamine-Glutamate-γ-aminobutyric acid (GlnGluGABA) metabolic cycle in the hippocampus, leading to neurotoxicity. We established an in vitro astrocyte Gad1 overexpression (OEX) model and found that the cultured medium from Gad1 OEX astrocytes reversed neuronal synaptic damage and the expression of gamma-aminobutyric acid (GABA) related receptors. Using the astrocyte Gad1 OEX mouse model, results showed that OEX of Gad1 ameliorated depressive-like behavior and cognitive dysfunction in mice. These findings provide new insight into the important role of GAD1 mediated GlnGluGABA metabolism disorder in Mn exposure induced depressive-like behavior. This study offers a novel sight to understanding abnormal emotional states following central nervous system damage induced by Mn exposure.

中文翻译：

锰暴露通过破坏 Gln-Glu-GABA 代谢周期导致抑郁样行为

长期锰（Mn）暴露与帕金森病样疾病（PD）之间存在相关性，抑郁症是 PD 的早期症状。然而，锰暴露与抑郁症之间的直接关系以及所涉及的机制仍不清楚。我们发现 Mn 暴露导致小鼠出现抑郁样行为和轻度认知障碍，其中 Mn 主要积累在海马体的山茱萸 3 （CA3）区域。小鼠表现出神经元树突棘的减少和星形胶质细胞的损伤，特别是在 CA3 区域。空间代谢组学显示，Mn 下调星形胶质细胞中谷氨酸脱羧酶 1 （GAD1）的表达，破坏海马体中的谷氨酰胺-谷氨酸-γ-氨基丁酸（GlnGluGABA）代谢循环，导致神经毒性。我们建立了体外星形胶质细胞 Gad1 过表达（OEX）模型，发现 Gad1 OEX 星形胶质细胞的培养培养基逆转了神经元突触损伤和 γ-氨基丁酸（GABA）相关受体的表达。使用星形胶质细胞 Gad1 OEX 小鼠模型，结果显示 Gad1 的 OEX 改善了小鼠的抑郁样行为和认知功能障碍。这些发现为 GAD1 介导的 GlnGluGABA 代谢紊乱在 Mn 暴露诱导的抑郁样行为中的重要作用提供了新的见解。这项研究为理解 Mn 暴露引起的中枢神经系统损伤后的异常情绪状态提供了一种新的视野。

更新日期：2024-09-10

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