Cited by 209Neurogenesis and neuroplasticity mechanismsStress Responses and CortisolTreatment of Major Depression

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

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Garza, J C, Guo, M, Zhang, W, Lu, X-Y·2012·Molecular Psychiatry

Abstract

Stress and glucocorticoid stress hormones inhibit neurogenesis, whereas antidepressants increase neurogenesis and block stress-induced decrease in neurogenesis. Our previous studies have shown that leptin, an adipocyte-derived hormone with antidepressant-like properties, promotes baseline neurogenesis in the adult hippocampus. This study aimed to determine whether leptin is able to restore 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 a delayed long-lasting antidepressant-like effect in the forced swim 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 glycogen synthase kinase-3β (GSK-3β) and β-catenin. While DEX decreased Ser9 phosphorylation and increased Tyr216 phosphorylation of GSK-3β, leptin increased Ser9 phosphorylation and attenuated the effects of DEX at both Ser9 and Tyr216 phosphorylation sites of GSK-3β. Moreover, leptin increased total level and nuclear translocation of β-catenin, a primary substrate of GSK-3β and a key regulator in controlling hippocampal neural progenitor cell proliferation, and reversed the inhibitory effects of DEX on β-catenin. Taken 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 GSK-3β/β-catenin signaling pathway.

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Authors
Garza, J. C., Guo, M., Zhang, W., & Lu, X.-Y.
Affiliations
The University of Texas at San Antonio Health Science Center (US)
Corresponding author
Lu, X-Y
ORCID
Guo, M
Venue
Molecular Psychiatry
Published
2011-12-20
Volume
17
Issue
8
Pages
790-808
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
OpenAlex
W2044506930
Cited by
209
References
160
Citations by year
2026: 4 · 2025: 9 · 2024: 4 · 2023: 9 · 2022: 19 · 2021: 15 · 2020: 23 · 2019: 14 · 2018: 13 · 2017: 17 · 2016: 13 · 2015: 23 · 2014: 24 · 2013: 12 · 2012: 10
FWCI
4.83
Type
journal article
Language
en
Open access
Locations
  • Molecular Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Mental Health (MH073844, MH076929, R01MH076929, MH083442, R01MH073844, F31MH083442)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Keywords
leptin, adult hippocampal neurogenesis, depression, chronic unpredictable mild stress, glucocorticoids, dexamethasone, GSK3β, β-catenin, Wnt signaling, neural stem/progenitor cells, leptin receptor, glucocorticoid receptor, antidepressant-like behavior, forced swim test
MeSH terms
Glycogen Synthase Kinase 3 beta, Animals, Cells, Cultured, Depression, Dexamethasone, Disease Models, Animal, Hippocampus, Male, Phosphorylation, Recombinant Proteins, Stress, Psychological, Signal Transduction, Cranial Irradiation, Rats, Sprague-Dawley, Leptin, Glycogen Synthase Kinase 3, Cell Proliferation, beta Catenin, Rats, Neurogenesis

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