The Effect Of Glycogen Synthesis Kinase-3in The Ketamine-induced Activation Of The MTOR Signaling

Objective:Depression is a widespread disease that destroys the physical and psychological health of humans and the incidence of which is17%. It is a critical reason for disabling. A recent study found that ketamine, a N-methyl-D-aspartate (NMDA) receptor antagonist, can induce antidepressant actions within2hours and have a sustained actions for1week, moreover, it can be effective on resistant depressions. Although the underlying mechanisms of ketamine exerting antidepressant actions is unclear, the mammalian target of rapamycin (mTOR) signaling has been proved to be involved in the antidepressant action of ketamine. Meanwhile, one study focusing on glycogen synthesis kinase-3(GSK-3) has uncovered the necessity of inhibiting GSK-3in the process of ketamine exerting antidepressant actions. However, the exact role of GSK-3in this process is unknown. Therefore, the primary goal of our study is to observe the role of GSK-3in the activation of mTOR signaling by the administration of ketamin, and reveal the underlying mechanism of antidepressant action of ketamine.Methods:The rats are divided to five groups with six in each group:vehicle+vehicle (Group V), vehicle+ketamine (Group K), inhibitor of PI3K/Akt (LY294002)+ketamine (Group L), inhibitor of mTOR (rapamycin)+ketamine (Group R), inhibitor of S6K (PF4708671)+ketamine (Group P). The contents of p-GSK-3β、p-mTOR and p-p70S6K are detected in the prefrontal cortex of rats.Results:Compared to Group V, the immobility time of rats in Group K is significantly decreased (P<0.05), while compared to Group K, the immobility times of Group L, Group R and Group P are greatly enhanced (P<0.05). The expression of P-GSK30in Group L is reduced compared to Group V (P<0.05), and its expression in Group R and Group P doesn’t change compared to Group K (P>0.05). Meanwhile, the expressions of p-mTOR and p-p70S6K in Group K are enhanced compared to Group V (P<0.05), and their expressions in Group L are reduced comapred to Group K (P<0.05), while the expression of p-p70S6K in Group R is significantly declined compared to Group K (P<0.05).Conclusions:Low dose ketamine probably exerts antidepressant effect by phosphorylating PI3K/Akt, and then GSK-3, subsequently activating mTOR and its downstream factors, and ultimately turning on the protein transcription.