Microglial glutaminase 1 deficiency mitigates neuroinflammation associated depression

•Increased expression of GLS1 and inflammatory response in the prefrontal cortex of patients with major depressive disorders.•Lack of GLS1 in microglia ameliorated LPS-induced neuroinflammation, anxiety/depression-like behavior and reactive microglial three-dimensional structure in prefrontal cortex.•Anti-neuroinflammation of GLS1 deficient microglia was mediated by its co-operation with less reactive astrocytes.•Decreased levels of miR-666-3p and miR-7115-3p in the extracellular vesicles released from GLS1 deficient microglia resulted in less Serpina3n expression and thus suppressed astrocyte activation during neuroinflammation. Glutaminase 1 (GLS1) has recently been reported to be expressed in microglia and plays a crucial role in neuroinflamation. Significantly increased level of GLS1 mRNA expression together with neuroinflammation pathway were observed in postmortem prefrontal cortex from depressed patients. To find out the function of microglial GLS1 in depression and neuroinflammation, we generated transgenic mice (GLS1 cKO), postnatally losing GLS1 in microglia, to detect changes in the lipopolysaccharide (LPS)-induced depression model. LPS-induced anxiety/depression-like behavior was attenuated in GLS1 cKO mice, paralleled by a significant reduction in pro-inflammatory cytokines and an abnormal microglia morphological phenotype in the prefrontal cortex. Reduced neuroinflammation by GLS1 deficient microglia was a result of less reactive astrocytes, as GLS1 deficiency enhanced miR-666-3p and miR-7115-3p levels in extracellular vesicles released from microglia, thus suppressing astrocyte activation via inhibiting Serpina3n expression. Together, our data reveal a novel mechanism of GLS1 in neuroinflammation and targeting GLS1 in microglia may be a novel strategy to alleviate neuroinflammation-related depression and other disease.