GLT-1-1-Dependent Astrocyte Derived Lactate Mediates The Antidepressant Effect Of Ketamine

[Backgroud and Objective] Most of the current antidepressants have the disadvantages of delayed onset and poor efficacy.Ketamine has a rapid and sustained antidepressant effect,but its side effects limit its clinical application.Therefore,it is of great significance to elucidate the neuromolecular mechanism of ketamine's antidepressant effect.Currently,the antidepressant research of ketamine mainly focuses on neurons.From the perspective of neuron-astrocyte interaction,we tested the hypothesis that "GLT-1 dependent astrocyte-derived lactate mediates the antidepressant effect of ketamine",and revealed a new mechanism of antidepressant effects of ketamine.[Methods] Lactate levels in brain tissue were determined by colorimetric method;Glycogen phosphorylase a(GPa)in brain tissue was tested by Elisa to evaluate GP activation;Western Blot was used to detect the astrocytes activation markers Glial fibers acidic protein(GFAP),GLT-1 and GP protein expression level;Fluorocitrate(FC)was used to selectively inactivate astrocytes;L-alpha-aminoadipic acid(L-AAA)wasused to selectively clear astrocytes;GLT-1 selective inhibitor Dihydrokainic acid(DHK)was used to inhibite GLT-1 transport;GP selective inhibitor 1,4-dideoxy-1,4-imine-d-arabinitol(DAB)was used to inhibite GP catalytic activity;Antisense oligodeoxynucleotides were used to selectively knock down the levels of Monocarboxylate transporter 1and 4(MCT1 and MCT4);Forced swimming test was used to evaluate depression-like behavior in rats.[Results](1)Ketamine rapidly up-regulated the levels of lactate,GP activation,GFAP,GLT-1 and GP expression in the hippocampus of rats;(2)Inactivating or eliminating astrocytes antagonized the antidepressant effect of ketamine,and exogenous lactate rescued this effect;(3)Inhibiting GLT-1 antagonized the effects of ketamine on up-regulating GP activity,GFAP and GP expression levels in hippocampus and antidepression,and exogenous lactate rescued the antidepressant effect of ketamine;(4)Inhibiting GP antagonized the effects of ketamine on up-regulating lactate level in hippocampus and antidepression,and exogenous lactate rescued the antidepressant effect of ketamine;(5)Knocking down of MCT4 antagonized the antidepressant effect of ketamine,and exogenous lactate rescued this antagonistic effect;MCT1knockdown did not affect the antidepressant effect of ketamine.[Conclusion] Ketamine promotes the generation and release of astrocyte-derived lactate through GLT-1 dependent way and mediates itsantidepressant effect.