Abstract: Olfactory dysfunction is accompanied with anxiety- and depressive-like behaviors. Impaired neurogenesis in hippocampus and subventricular zone （SVZ）-olfactory bulb（OB） contribute to anxiety- and depressive behaviors and olfactory dysfunctions. However，the underlying mechanisms remain unclear. Adaptor proteins containing the pleckstrin homology domain，phosphotyrosine binding domain，and leucine zipper motif （APPLs） are involved in regulating many biological activities. APPL2 showed the potentials to modulate cell growth，but whether APPL2 could affect adult neurogenesis and animal mood behaviors remains unknown.Herein，we tested the hypothesis that APPL2 could affect glucocorticoid receptor （GR） signaling and modulate hippocampal neurogenesis，contributing to depressive and anxiety behaviors. APPL2 Tg mice had enhanced GR phosphorylation under basic condition but had no different plasma corticosterone （CORT） level and GR phosphorylation under stress stimulation. APPL2 Tg mice had decreased hippocampal neurogenesis that was reversed by GR antagonist RU486. APPL2 Tg mice had impaired hippocampal neurogenesis and depressive and anxiety behaviors. We further identified the roles of APPL2 in olfactory functions. APPL2 Tg mice displayed higher GR activity and less neurogenesis at olfactory system with less olfactory sensitivity than WT mice，indicating that APPL2 could be a potential therapeutic target for depression and olfactory deficits. We then studied the effects of baicalin，a natural antioxidant， on modulating APPL2/GR signaling pathway and promoting neurogenesis for antidepressant and improving olfactory functions. Baicalin inhibited APPL2/GR signaling pathway and improved neurogenesis at SVZ，OB， and hippocampus in APPL2 Tg mice and chronic corticosterone-induced depression mouse model. Baicalin attenuated depressive- and anxietylike behaviors and improved olfactory functions in chronic depression mouse model and APPL2 Tg mice. In conclusion，APPL2 could be a novel therapeutic target for improving depressant related olfactory dysfunctions. Antioxidant therapy with baicalin could inhibit APPL2-mediated GR hyperactivity and promote neurogenesis， releasing depressive and anxiety symptoms and improving olfactory functions.