Molecular Mechanism Of Rapid-acting Antidepressant GLYX-13,an NMDA Receptor Glycine Site Functional Partial Agonist

Objectives: Major depressive disorder(MDD)is a widespread psychiatric disorder that greatly influences public health.However,the existing antidepressants have the disadvantages of low efficiency,slow onset of action,and a large number of side effects.Therefore,it is urgent to develop fast and long-lasting effects of antidepressants.The clinical and preclinical studies revealed that a single dose of GLYX-13 can produce rapid and long-lasting antidepressant-like effects.Our previous study reported that the neuropeptide VGF(non-acronym)plays critical role in the rapid antidepressant-like effect of GLYX-13,and the antidepressant-like effects of GLYX-13 dependent on the α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid(AMPA)receptor activation and further up-regulation of the down-stream signaling pathway of Trk B receptormediated phosphatidylinositol 3-kinase(PI3K)/ Protein kinase B(PKB,also known as AKT)/mammalian target of rapamycin(m TOR)/ VGF.However,it remains unclear whether another signal transduction pathway mediated by the Trk B receptor: extracellular regulated protein kinases(ERK)/ m TOR / brain derived neurotrophic factor(BDNF)/ VGF is involved in the fasr-acting antidepressant-like actions of GLYX-13.Herein,our current study aimed to confirmed the rapidacting antidepressant-like actions of GLYX-13,and also to investigate the involvement of AMPA receptor and it’s down-stream ERK / m TOR / BDNF / VGF signaling in the rapid antidepressantlike effects of GLYX-13 in rodent models.Methods: The chronic social defeat stress(CSDS)and chronic unpredictable stress(CUS)depression mice models were used in our present study.Behavioral experiments such as open field test,sucrose preference test,forced swimming test and novelty suppressed feeding test were used to detect changes in locomotor activity and depression-like phenotype in mice,and the hippocampus and prefrontal cortex tissues of mice were taken for Western blotting and immunofluorescence staining.Results: We found that a single injection of GLYX-13(10mg/kg)significantly reversed CSDS-induced depression-like behaviors in mice and down-regulation of VGF and pTrkB in the brain.However,pretreatment of AMPA receptor antagonist NBQX could block the antidepressant effect of GLYX-13 and block the up-regulation of VGF and pTrkB by GLYX-13.In addition,GLYX-13 reversed CUS-induced depression-like behaviors and down-regulation of pERK1/2(Thr204/187),p-mTOR(Ser2448),p-p70S6K(Thr389),P-4E-BP1(Thr37/46),BDNF and VGF protein expressions in the hippocampus and prefrontal cortex of the mouse brain in a dosedependent manner.Further,PD98059,an ERK signaling pathway blocker,significanly blocked the antidepressant-like effects of GLYX-13 and the up-regulation of p-ERK1/2(Thr204/187),pm TOR(Ser2448),p-p70S6K(Thr389),p-4E-BP1(Thr37/46),BDNF and VGF in the prefrontal cortex and hippocampal of mice.Conclusions: Our results further confirmed that GLYX-13’s rapid antidepressant effect depends on AMPA receptor activation.The antidepressant effect of GLYX-13 depends on the upregulation of BDNF and VGF mediated by ERK / m TOR signaling pathway.Our study provide theoretical basis for the novel rapid antidepressants candidate development based on NMDA receptor allosteric regulation.