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Cited by 115Neurogenesis and neuroplasticity mechanismsNeuroscience and Neuropharmacology ResearchWnt/β-catenin signaling in development and cancer

Blocked Inhibitory Serine-Phosphorylation of Glycogen Synthase Kinase-3α/β Impairs In Vivo Neural Precursor Cell Proliferation

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Eom, Tae-Yeon, Jope, Richard S.·2009·Biological Psychiatry
DOI 10.1016/j.biopsych.2009.04.015PMC PMC2746934
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Abstract

Background Adult neurogenesis augments neuronal plasticity, and deficient neurogenesis might contribute to mood disorders and schizophrenia and impede treatment responses. Because these diseases might be associated with inadequately controlled glycogen synthase kinase-3 (GSK3), we tested whether blocked inhibitory serine-phosphorylation of GSK3 impairs neurogenesis. Methods Neural precursor cell (NPC) proliferation was measured by dentate gyrus bromodeoxyuridine (BrdU) labeling in GSK3alpha/beta(21A/21A/9A/9A) knockin mice with serine-to-alanine mutations to block inhibitory serine-phosphorylation of GSK3 while it remains within the physiological range, because GSK3 is not overexpressed. Results There was a drastic 40% impairment in neurogenesis in vivo in GSK3 knockin mice compared with wild-type mice. Impaired neurogenesis could be due to effects of GSK3 in NPCs or in surrounding cells that modulate NPCs. In vitro proliferation was equivalent for NPCs from GSK3 knockin and wild-type mice, suggesting an in vivo deficiency in GSK3 knockin mice of external support for NPC proliferation. Measurements of two neurotrophins that promote neurogenesis demonstrated less hippocampal vascular endothelial growth factor but not brain-derived growth factor in GSK3 knockin mice than wild-type mice, reinforcing the possibility that insufficient environmental support in GSK3 knockin mice might contribute to impaired neurogenesis. In vivo chronic co-administration of lithium and fluoxetine, which each increase inhibitory serine-phosphorylation of wild-type GSK3, increased NPC proliferation in wild-type but not GSK3 knockin mice. Conclusions Blocked inhibitory control of GSK3 impaired neurogenesis and the capacity of therapeutic drugs to stimulate neurogenesis, likely through deficient environmental factors that support neurogenesis, which might contribute to psychiatric diseases and responses to therapeutic drugs.

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  • GSK3 knockin mice express normal levels of both GSK3 isoforms, GSK3α and GSK3β, but with serine-to-alanine mutations, S9A-GSK3β and S21A-GSK3α, to maintain GSK3 maximally active.

    “GSK3 knockin mice express normal levels of both GSK3 isoforms, GSK3α and GSK3β, but with serine-to-alanine mutations, S9A-GSK3β and S21A-GSK3α, to maintain GSK3 maximally active, since it cannot be inhibited by serinephosphorylation (43, 44).”

    From Inflammatory T helper 17 cells promote depression-like behavior in mice (2013) · cites this paper as [44]

    The Introduction (page unavailable) describes the S9A-GSK3β and S21A-GSK3α mutations, normal expression of both isoforms, and the resulting inability to inhibit GSK3 by serine phosphorylation. The Results confirm normal total levels of both isoforms, but the paper does not establish that GSK3 is maximally active; it establishes that this particular inhibitory mechanism is blocked. (LLM, conf=0.86)

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Authors
Eom, T.-Y., & Jope, R. S.
Affiliations
University of Alabama at Birmingham (US)
Corresponding author
Jope, Richard S.
ORCID
Eom, Tae-Yeon
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2009-09
Volume
66
Issue
5
Pages
494-502
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2009.04.015
PMC
PMC2746934
OpenAlex
W2005633501
Cited by
115
References
7
Citations by year
2026: 1 · 2024: 4 · 2023: 3 · 2022: 4 · 2021: 8 · 2020: 6 · 2019: 4 · 2018: 7 · 2017: 5 · 2016: 9 · 2015: 9 · 2014: 3 · 2013: 14 · 2012: 13
FWCI
3.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
Keywords
glycogen synthase kinase-3, adult neurogenesis, neural progenitor proliferation, dentate gyrus, neurotrophins, vascular endothelial growth factor, lithium, fluoxetine, mood disorders, schizophrenia
MeSH terms
Animals, Drug Interactions, Fluoxetine, Hippocampus, Isoenzymes, Lithium, Male, Mice, Inbred Strains, Mutation, Phosphorylation, Serine, Stem Cells, Brain-Derived Neurotrophic Factor, Glycogen Synthase Kinase 3, Vascular Endothelial Growth Factor A, Cell Proliferation, Mice, Embryonic Stem Cells, Neurogenesis, Gene Knock-In Techniques, In Vitro Techniques

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