GLT1-dependent Astrocyte Glycogenic Lactic Acid Mediates The Antidepressant Effect Of Apelin-13

Objective:The incidence rate of depression is high,which has social and personal harm.The search for new antidepressants has important potential clinical significance.Our research group has confirmed that Apelin-13 acts antidepressant effect,but its mechanism is far from clear.The studies have found that exogenous increased intracranial lactic acid has antidepressant effects.Astrocytes are an important source of lactic acid in the brain,and Glutamate transporter 1(GLT1)can drive the aerobic glycolysis of astrocytes to generate lactic acid.Glycogen only exists in astrocytes and participates in aerobic glycolysis catalyzed by Glycogen phosphorylase(GP).Our previous experiments showed that Apelin-13 could up-regulate the expression level of GLT1.This study investigated the mediating effect of glt1-dependent astrocyte glycogenic lactic acid on the antidepressant effect of Apelin-13.Methods: Forced swimming test was used to evaluate depressive behavior,and open field test was used to evaluate spontaneous activity of rats.Colorimetric method was used to detect the lactate level in hippocampus.Western Blot was used to detect the expression levels of GLT1,GP,Brain derived neurotrophic factor(BDNF)and P11 in hippocampus.Results: 1.Injection of apelin-13 into the lateral ventricle up-regulated the expression levels of GLT1,GP,BDNF,P11 and lactic acid in the hippocampus.2.GLT1 inhibitor Ydrokainic acid(DHK)blocked the effects of apelin-13 that up-regulate the expression of GP,BDNF and P11 in hippocampal and its antidepressant effect;3.The inhibitor of glycogen phosphorylase1,4-dideoxy-1,4-imino-D-arabinitol(DAB)blocked the effect of Apelin-13 that up-regulate the expression of BDNF and P11 in hippocampus and its antidepressant effect;4.Exogenous lactic acid can rescue the blocking effect of DHK and DAB on the antidepressant effect of Apelin-13.Conclusion: Apelin-13 exerts the antidepressant effect by GLT1up-regulating the expression of GP to promote the formation of glycogenic lactic acid in astrocytes...