Microglial glutaminase 1 mediates chronic restraint stress-induced depression-like behaviors and synaptic damages

Dear Editor,Major depressive disorder(MDD)is one of the most common psychiatric illnesses that significantly increase the risk of suicide.1 Stress-triggered dysfunctions of microglia have been identified as a commonly occurred pathological feature of MDD.1–3 Microglial dysfunction contributes to the pathogenesis of MDD via immunoresponses/neuroinflammation-mediated neural damage and pathological synapse loss-mediated neural circuit disruption.1 Although the involvement of microglia in MDD has been widely investigated,the molecular mechanisms underlying microglial dysfunction remain largely unknown.Recently,we identified glutaminase 1(Gls1)as one key protein that participates in microglial dysfunction.4–6 Gls1 catalyzes the hydrolysis of glutamine to produce glutamate in the brain.4 Besides its well-known role in excitatory neurotoxicity,we found Gls1 up-regulation in microglia in animal models of Alzheimer’s disease and ischemic stroke.4,7 Gls1 activates microglia to overproduce cytokines and release inflammatory extracellular vesicles,therefore leading to neuroinflammation in animal models of Alzheimer’s disease and ischemic stroke.4–6 More importantly,Gls1 has been found to be up-regulated in the brains of MDD patients,and microglial Gls1 deficiency mitigated LPS-induced depression-like behaviors.8 However,LPS exposure is not an appropriate model to mimic MDD phenotypes,leaving the involvement of Gls1 in MDD an undetermined question.