More studies suggest that neuropeptide VGF(non-acryonimic)and PI3K/AKT/mTOR signaling play pivotal role in depression.However,whether the PI3K/AKT/mTOR signaling-mediated VGF in hippocampus participates in the rapid-acting antidepressant-like actions of GLYX-13 is unclear.Herein,we evaluated the effects of a acute GLYX-13(0.5,5 and 10 mg/kg,i.p.)treatment 60 min prior to the forced swim test(FST).In addition,we assessed whether the acute treatment with GLYX-13 reverses the depressive-like behaviors induced by chronic unpredictable mild stress(CUMS)in mice.Furthermore,we determined whether the Vgf knock-down in hippocampus of mice blocks the effects of GLYX-13.Moreover,we also demonstrated the effects of intra-hippocampus(i.h.)infusions of LY294002(10nmol/side),a specific phosphatidylinositol 3-kinase(PI3K)inhibitor 30 min prior to the treatment of GLYX-13(i.p.)in FST.Lastly,neurochemical parameters related to PI3K/AKT/mTOR signaling and VGF in hippocampus of mice were examined.Our results shown that administration of GLYX-13 dose-dependently reduced immobility time in FST.Similarly,GLYX-13 dose-dependently reversed the CUMS-induced depressive-like behaviors in FST.In addition,GLYX-13 significantly reversed the down-regulation on phosphorylation of AKT(pAKT),mTOR(pmTOR)and eukaryotic elongation factor 2(peEF2)and VGF induced by CUMS in hippocampus of mice.Further,Vgf knock-down in hippocampus of mice significantly blocked the rapid-acting antidepressant-like effects and up-regulation on PI3K/AKT/mTOR signaling of GLYX-13.Finally,i.h.infusions of LY294002 significantly blocked the antidepressant-like effects and up-regulation on PI3K/AKT/mTOR/VGF signaling of GLYX-13.Together,our results suggest that PI3K/AKT/mTOR signaling-mediated VGF in hippocampus is involved in the antidepressant-like effects of GLYX-13.