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

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.