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

Tae Yeon Eom, Richard S Jope

Research output: Contribution to journalArticle

79 Citations (Scopus)

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 GSK3α/β21A/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.

Original languageEnglish
Pages (from-to)494-502
Number of pages9
JournalBiological Psychiatry
Volume66
Issue number5
DOIs
StatePublished - Sep 1 2009
Externally publishedYes

Fingerprint

Glycogen Synthase Kinase 3
Serine
Neurogenesis
Phosphorylation
Cell Proliferation
Neuronal Plasticity
Fluoxetine
Dentate Gyrus
Nerve Growth Factors
Bromodeoxyuridine
Mood Disorders
Lithium
Alanine
Pharmaceutical Preparations

Keywords

  • Fluoxetine
  • glycogen synthase kinase-3
  • lithium
  • mood disorders
  • neural precursor cells
  • neurogenesis

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Blocked Inhibitory Serine-Phosphorylation of Glycogen Synthase Kinase-3α/β Impairs In Vivo Neural Precursor Cell Proliferation. / Eom, Tae Yeon; Jope, Richard S.

In: Biological Psychiatry, Vol. 66, No. 5, 01.09.2009, p. 494-502.

Research output: Contribution to journalArticle

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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 GSK3α/β21A/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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N2 - 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 GSK3α/β21A/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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