A Preliminary Study On Glutamatergic Neurotransmitter In The Prefrontal Cortex Among Chronic Social Defeat Stress Mice Model Of Depression

BACKGROUND Depression is a serious complication of mental illness with high morbidity and mortality.The World Health Organization(WHO)has reported that the number of patients with global depression has reached 322 million.So far,the pathogenesis has been reported to include HPA axis disorders,monoamine and GABAergic neurotransmitter disorders,and BDNF abnormal expression theory.However,the pathogenes is of depression is still complex and unknown.Therefore,it is important to actively look for the pathogenesis of depression.In the past,it has been found that glutamate neurotransmitters play an important role in the study of neuropsychiatric disorders,and it is worth considering the study of the pathogenesis and drug target of new depression.The prefrontal cortex is a key brain area that regulates mood,memory and cognition,and has been involved in the pathogenesis of depression for decades.Although previous studies have used the screening of metabolites to measure changes in neurotransmitters in depression,the above-mentioned non-quantitative methods do not accurately quantify the changes in metabolic processes.To overcome this problem,we used LC-MS/MS method to quantitatively detect 25 neurotransmitters and related metabolites of three highly metabolic pathways of depression.OBJECTIVE The key neurotransmitters of tryptophan pathway,GABA pathway a nd catecholamine pathway were quantitatively detected in the prefrontal cortex by LC-MS/MS method.And further to the differential metabolic substances related mechanisms to verify and explore.METHODS 1.The model of social depression and depression in mice was established,and their behavior was evaluated.The mice were divided into depression group,resistance group and control group according to the social interaction ratio 2.LC-MS/MS analysis was performed on the prefrontal cortex of 10 groups of mice,and the key neurotransmitters were analyzed for the three channels of tryptophan pathway,GABA pathway and catecholamine pathway.3.RT-PCR and Western Blotting validation of the neurotransmitterassociated upstream and downstream metabolites were performed on the basis of LC-MS/MS results.RESULTS1.The social interaction test was used to evaluate the depression and resistance phenotype of the defeated mice.Thirteen(46.4%)mice showed depressive resistance phenotype.The SI value of depression mice was lower than that of the control group and the res istance group,the SI value of the resistance group was significantly higher than that of the control group and the depression group 2.The levels of glutamate were significantly reduced in the depression and resistance groups,and L-DOPA and VMA showed a significant increase in depression compared with the control and resistance groups 3.The glutamate metabolic pathway demonstrated that m RNA expression at the gene expression levels Glul,Gad1,Gad2 and m Glu R1 was significantly altered in the CSDS group compared to the control group.At the protein level,Glu A1 was altered in CSDS mice compared to the control group,but no significant changes were found in EAAT2 and Glul.CONCLUSION The results show that the metabolic pathway of excitatory glutamate has an important effect on the prefrontal cortex of social frustration model.Targeted metabolomics tests revealed significant changes in levels of glutamate,L-DOPA and VMA.The change in glutamate in the LC-MS/MS assay is related to the level of gene and protein in the metabolic pathway.While further research needs to confirm these findings,the key glutamate can operate by circuits that may produce pharmacological effects of depressive disorders that can help find more diagnostic tools for this disease.