Leptin restores adult hippocampal neurogenesis in a chronic unpredictable stress model of depression and reverses glucocorticoid-induced inhibition of GSK-3β/β-catenin signaling

Abstract

Stress and glucocorticoid stress hormones inhibit neurogenesis, whereas antidepressants increase neurogenesis and block stress-induced decrease of neurogenesis. Our previous studies have shown leptin, an adipocyte-derived hormone with antidepressant-like properties 1, promotes baseline neurogenesis in the adult hippocampus 2. The present study aimed to determine whether leptin is able to restore stress-induced suppression of neurogenesis in a rat chronic unpredictable stress (CUS) model of depression. Chronic treatment with leptin reversed the CUS-induced reduction of hippocampal neurogenesis and depression-like behaviors. Leptin treatment elicited delayed long-lasting antidepressant-like effects in the behavioral despair test, and this effect was blocked by ablation of neurogenesis with X-irradiation. The functional isoform of the leptin receptor, LepRb, and the glucocorticoid receptor (GR) were colocalized in hippocampal neural stem/progenitor cells in vivo and in vitro. Leptin treatment reversed the GR agonist dexamethasone (DEX)-induced reduction of proliferation of cultured neural stem/progenitor cells from adult hippocampus. Further mechanistic analysis revealed that leptin and DEX converged on GSK3β and β-catenin. DEX decreased Ser9 phosphorylation and increased Tyr216 phosphorylation of GSK3β, while leptin increased Ser9 phosphorylation and attenuated the effects of DEX at both Ser9 and Tyr216 phosphorylation sites of GSK3β. Moreover, leptin increased total level and nuclear translocation of β-catenin, a primary substrate of GSK3 β and a key regulator in controlling neural progenitor proliferation, and reversed the inhibitory effects of DEX on β-catenin. Together, our results suggest that adult neurogenesis is involved in the delayed long-lasting antidepressant-like behavioral effects of leptin, and leptin treatment counteracts chronic stress and glucocorticoid-induced suppression of hippocampal neurogenesis via activating the GSK3β/β-catenin signaling pathway.

Timosaponin B-III exhibits antidepressive activity in a mouse model of postpartum depression by the regulation of inflammatory cytokines, BNDF signaling and synaptic plasticity

“…BNDF plays an important role in depression and direct hippocampal BNDF infusions have been shown to produce antidepressive effects in rodents (27); thus, antidepressants may exert therapeutic effects by increasing BDNF levels (28). GSK-3β demonstrated antidepressive activity in a chronic unpredictable stress model of depression (29). Synaptic plasticity, for which GluR1, PSD95 and synapsin I are required for maintenance (30), plays an important role in the pathophysiology of depression; thus, antidepressants may also exert therapeutic effects by regulating synaptic plasticity-related signaling (31).…”

Mice with ablated adult brain neurogenesis are not impaired in antidepressant response to chronic fluoxetine

“…Finally, the prevailing perception in the literature, suggests FST to be a proper test to show neurogenesis-dependence of antidepressant efficacy. Several groups described X-irradiation to block antidepressant effects using FST (e.g., Zhu et al, 2010;Garza et al, 2012) while correlative observations linking antidepressant treatment effects in FST and adult hippocampal neurogenesis have been reported numerous times (Liu et al, 2008;Silva et al, 2008;Schmidt and Duman, 2010;Wainwright et al, 2011;Wang et al, 2011;Jiang et al, 2012;Lin and Wang, 2014;Lu et al, 2014).…”

Beneficial Effect of Leptin on Spatial Learning and Memory in Streptozotocin-Induced Diabetic Rats

“…Because neural stem/ progenitor cells co-express both glucocorticoid receptors (GR) and leptin receptor b, it is possible that they have interactions with each other (28) and to control hippocampal health and homeostasis (29). Leptin inhibits the detrimental effects of chronic stress and the resultant elevated levels of glucocorticoids on neurogenesis and behavior (28), in addition to positive effects on the spatial memory by reducing the anxiety (24), which may at least partly play a role in the results of the present study.…”

“…Because neural stem/ progenitor cells co-express both glucocorticoid receptors (GR) and leptin receptor b, it is possible that they have interactions with each other (28) and to control hippocampal health and homeostasis (29). Leptin inhibits the detrimental effects of chronic stress and the resultant elevated levels of glucocorticoids on neurogenesis and behavior (28), in addition to positive effects on the spatial memory by reducing the anxiety (24), which may at least partly play a role in the results of the present study. Furthermore, leptin induces aromatase expression in adipose tissue followed by the elevation of estrogen (30); estrogen and its receptors are involved in learning, so the effect of leptin on memory may in part be due to its effects on estrogen (31) through the increased amounts of nitric oxide and acetylcholine in the brain (32).…”