Advertisement

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

  • Tae-Yeon Eom
    Affiliations
    Department of Psychiatry, Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama
    Search for articles by this author
  • Richard S. Jope
    Correspondence
    Address correspondence to Richard S. Jope, Ph.D., Department of Psychiatry and Behavioral Neurobiology, 1720 Seventh Avenue South, Sparks Center 1057, University of Alabama at Birmingham, Birmingham, AL 35294-0017
    Affiliations
    Department of Psychiatry, Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama
    Search for articles by this author

      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.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Lie D.C.
        • Song H.
        • Colamarino S.A.
        • Ming G.L.
        • Gage F.H.
        Neurogenesis in the adult brain: New strategies for central nervous system diseases.
        Annu Rev Pharmacol Toxicol. 2004; 44: 399-421
        • Abrous D.N.
        • Koehl M.
        • Le Moal M.
        Adult neurogenesis: from precursors to network and physiology.
        Physiol Rev. 2005; 85: 523-569
        • Jacobs B.L.
        • Praag H.
        • Gage F.H.
        Adult brain neurogenesis and psychiatry: A novel theory of depression.
        Mol Psychiatry. 2000; 5: 262-269
        • Duman R.S.
        • Malberg J.
        • Nakagawa S.
        • D'Sa C.
        Neuronal plasticity and survival in mood disorders.
        Biol Psychiatry. 2000; 48: 732-739
        • Kempermann G.
        Regulation of adult hippocampal neurogenesis—implications for novel theories of major depression.
        Bipolar Disord. 2002; 4: 17-33
        • Schloesser R.J.
        • Chen G.
        • Manji H.K.
        Neurogenesis and neuroenhancement in the pathophysiology and treatment of bipolar disorder.
        Int Rev Neurobiol. 2007; 77: 143-178
        • Reif A.
        • Fritzen S.
        • Finger M.
        • Strobel A.
        • Lauer M.
        • Schmitt A.
        • Lesch K.P.
        Neural stem cell proliferation is decreased in schizophrenia, but not in depression.
        Mol Psychiatry. 2006; 11: 514-522
        • Malberg J.E.
        • Eisch A.J.
        • Nestler E.J.
        • Duman R.S.
        Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus.
        J Neurosci. 2000; 20: 9104-9110
        • Czeh B.
        • Michaelis T.
        • Watanabe T.
        • Frahm J.
        • de Biurrun G.
        • van Kampen M.
        • et al.
        Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine.
        Proc Natl Acad Sci U S A. 2001; 98: 12796-12801
        • Manev H.
        • Uz T.
        • Smalheiser N.R.
        • Manev R.
        Antidepressants alter cell proliferation in the adult brain in vivo and in neural cultures in vitro.
        Eur J Pharmacol. 2001; 411: 67-70
        • Banasr M.
        • Soumier A.
        • Hery M.
        • Mocaer E.
        • Daszuta A.
        Agomelatine, a new antidepressant, induces regional changes in hippocampal neurogenesis.
        Biol Psychiatry. 2006; 59: 1087-1096
        • Warner-Schmidt J.L.
        • Duman R.S.
        VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants.
        Proc Natl Acad Sci U S A. 2007; 104: 4647-4652
        • Scott B.W.
        • Wojtowicz J.M.
        • Burnham W.M.
        Neurogenesis in the dentate gyrus of the rat following electroconvulsive shock seizures.
        Exp Neurol. 2000; 165: 231-236
        • Madsen T.M.
        • Treschow A.
        • Bengzon J.
        • Bolwig T.G.
        • Lindvall O.
        • Tingstrom A.
        Increased neurogenesis in a model of electroconvulsive therapy.
        Biol Psychiatry. 2000; 47: 1043-1049
        • Segi-Nishida E.
        • Warner-Schmidt J.L.
        • Duman R.S.
        Electroconvulsive seizure and VEGF increase the proliferation of neural stem-like cells in rat hippocampus.
        Proc Natl Acad Sci U S A. 2008; 105: 11352-11357
        • Warner-Schmidt J.L.
        • Madsen T.M.
        • Duman R.S.
        Electroconvulsive seizure restores neurogenesis and hippocampus-dependent fear memory after disruption by irradiation.
        Eur J Neurosci. 2008; 27: 1485-1493
        • Chen G.
        • Rajkowska G.
        • Du F.
        • Seraji-Bozorgzad N.
        • Manji H.K.
        Enhancement of hippocampal neurogenesis by lithium.
        J Neurochem. 2000; 75: 1729-1734
        • Hashimoto R.
        • Senatorov V.
        • Kanai H.
        • Leeds P.
        • Chuang D.M.
        Lithium stimulates progenitor proliferation in cultured brain neurons.
        Neuroscience. 2003; 117: 55-61
        • Shimomura A.
        • Nomura R.
        • Senda T.
        Lithium inhibits apoptosis of mouse neural progenitor cells.
        Neuroreport. 2003; 14: 1779-1782
        • Dawirs R.R.
        • Hildebrandt K.
        • Teuchert-Noodt G.
        Adult treatment with haloperidol increases dentate granule cell proliferation in the gerbil hippocampus.
        J Neural Transm. 1998; 105: 317-327
        • Wakade C.G.
        • Mahadik S.P.
        • Waller J.L.
        • Chiu F.C.
        Atypical neuroleptics stimulate neurogenesis in adult rat brain.
        J Neurosci Res. 2002; 69: 72-79
        • Wang H.D.
        • Dunnavant F.D.
        • Jarman T.
        • Deutch A.Y.
        Effects of antipsychotic drugs on neurogenesis in the forebrain of the adult rat.
        Neuropsychopharmacology. 2004; 29: 1230-1238
        • Newton S.S.
        • Duman R.S.
        Neurogenic actions of atypical antipsychotic drugs and therapeutic implications.
        CNS Drugs. 2007; 21: 715-725
        • Santarelli L.
        • Saxe M.
        • Gross C.
        • Surget A.
        • Battaglia F.
        • Dulawa S.
        • et al.
        Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants.
        Science. 2003; 301: 805-809
        • Schänzer A.
        • Wachs F.P.
        • Wilhelm D.
        • Acker T.
        • Cooper-Kuhn C.
        • Beck H.
        • et al.
        Direct stimulation of adult neural stem cells in vitro and neurogenesis in vivo by vascular endothelial growth factor.
        Brain Pathol. 2004; 14: 237-248
        • Le Bras B.
        • Barallobre M.J.
        • Homman-Ludiye J.
        • Ny A.
        • Wyns S.
        • Tammela T.
        • et al.
        VEGF-C is a trophic factor for neural progenitors in the vertebrate embryonic brain.
        Nat Neurosci. 2006; 9: 340-348
        • Muller S.
        • Chakrapani B.P.
        • Schwegler H.
        • Hofmann H.D.
        • Kirsch M.
        Neurogenesis in the dentate gyrus depends on CNTF and STAT3 signaling.
        Stem Cells. 2009; 27: 431-441
        • Li Y.
        • Luikart B.W.
        • Birnbaum S.
        • Chen J.
        • Kwon C.H.
        • Kernie S.G.
        • et al.
        TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment.
        Neuron. 2008; 59: 399-412
        • Scharfman H.
        • Goodman J.
        • Macleod A.
        • Phani S.
        • Antonelli C.
        • Croll S.
        Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats.
        Exp Neurol. 2005; 192: 348-356
        • Bartkowska K.
        • Paquin A.
        • Gauthier A.S.
        • Kaplan D.R.
        • Miller F.D.
        Trk signaling regulates neural precursor cell proliferation and differentiation during cortical development.
        Development. 2007; 134: 4369-4380
        • Nibuya M.
        • Morinobu S.
        • Duman R.S.
        Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments.
        J Neurosci. 1995; 15: 7539-7547
        • Chen B.
        • Dowlatshahi D.
        • MacQueen G.M.
        • Wang J.F.
        • Young L.T.
        Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication.
        Biol Psychiatry. 2001; 50: 260-265
        • Balu D.T.
        • Hoshaw B.A.
        • Malberg J.E.
        • Rosenzweig-Lipson S.
        • Schechter L.E.
        • Lucki I.
        Differential regulation of central BDNF protein levels by antidepressant and non-antidepressant drug treatments.
        Brain Res. 2008; 23: 37-43
        • Jope R.S.
        • Roh M.S.
        Glycogen synthase kinase-3 (GSK3) in psychiatric diseases and therapeutic interventions.
        Curr Drug Targets. 2006; 7: 1421-1434
        • Klein P.S.
        • Melton D.A.
        A molecular mechanism for the effect of lithium on development.
        Proc Natl Acad Sci U S A. 1996; 93: 8455-8459
        • Stambolic V.
        • Ruel L.
        • Woodgett J.R.
        Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signaling in intact cells.
        Curr Biol. 1996; 6: 1664-1668
        • Jope R.S.
        Anti-bipolar therapy: Mechanism of action of lithium.
        Mol Psychiatry. 1999; 4: 117-128
        • Li X.
        • Zhu W.
        • Roh M.S.
        • Friedman A.B.
        • Rosborough K.M.
        • Jope R.S.
        In vivo regulation of glycogen synthase kinase-3β (GSK3β) by serotonergic activity in mouse brain.
        Neuropsychopharmacology. 2004; 29: 1426-1431
        • Kang U.G.
        • Seo M.S.
        • Roh M.S.
        • Kim Y.
        • Yoon S.C.
        • Kim Y.S.
        The effects of clozapine on the GSK-3-mediated signaling pathway.
        FEBS Lett. 2004; 560: 115-119
        • Alimohamad H.
        • Rajakumar N.
        • Seah Y.H.
        • Rushlow W.
        Antipsychotics alter the protein expression levels of beta-catenin and GSK-3 in the rat medial prefrontal cortex and striatum.
        Biol Psychiatry. 2005; 57: 533-542
        • Li X.
        • Rosborough K.M.
        • Friedman A.B.
        • Zhu W.
        • Roth K.A.
        Regulation of mouse brain glycogen synthase kinase-3 by atypical antipsychotics.
        Int J Neuropsychopharmacology. 2007; 10: 7-19
        • Roh M.S.
        • Seo M.S.
        • Kim Y.
        • Kim S.H.
        • Jeon W.J.
        • Ahn Y.M.
        • et al.
        Haloperidol and clozapine differentially regulate signals upstream of glycogen synthase kinase 3 in the rat frontal cortex.
        Exp Mol Med. 2007; 39: 353-360
        • Gould E.
        Serotonin and hippocampal neurogenesis.
        Neuropsychopharmacology. 1999; 21: S46-S51
        • Eom T.Y.
        • Roth K.A.
        • Jope R.S.
        Neural precursor cells are protected from apoptosis induced by trophic factor withdrawal or genotoxic stress by inhibitors of glycogen synthase kinase 3.
        J Biol Chem. 2007; 282: 22856-22864
        • Blaschke A.J.
        • Staley K.
        • Chun J.
        Widespread programmed cell death in proliferative and postmitotic regions of the fetal cerebral cortex.
        Development. 1996; 122: 1165-1174
        • Thomaidou D.
        • Mione M.C.
        • Cavanagh J.F.
        • Parnavelas J.G.
        Apoptosis and its relation to the cell cycle in the developing cerebral cortex.
        J Neurosci. 1997; 17: 1075-1085
        • Kuhn H.G.
        • Biebl M.
        • Wilhelm D.
        • Li M.
        • Friedlander R.M.
        • Winkler J.
        Increased generation of granule cells in adult Bcl-2-overexpressing mice: A role for cell death during continued hippocampal neurogenesis.
        Eur J Neurosci. 2005; 22: 1907-1915
        • Jope R.S.
        • Johnson G.V.W.
        The glamour and gloom of glycogen synthase kinase-3 (GSK3).
        Trends Biochem Sci. 2004; 29: 95-102
        • McManus E.J.
        • Sakamoto K.
        • Armit L.J.
        • Ronaldson L.
        • Shpiro N.
        • Marquez R.
        • Alessi D.R.
        Role that phosphorylation of GSK3 plays in insulin and Wnt signaling defined by knockin analysis.
        EMBO J. 2005; 24: 1571-1583
        • Akhtar R.S.
        • Geng Y.
        • Klocke B.J.
        • Roth K.A.
        Neural precursor cells possess multiple p53-dependent apoptotic pathways.
        Cell Death Differ. 2006; 13: 1727-1739
        • Eisch A.J.
        • Barrot M.
        • Schad C.A.
        • Self D.W.
        • Nestler E.J.
        Opiates inhibit neurogenesis in the adult rat hippocampus.
        Proc Natl Acad Sci U S A. 2000; 97: 7579-7584
        • Bradford M.M.
        A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding.
        Anal Biochem. 1976; 72: 248-254
        • Nakagawa S.
        • Kim J.E.
        • Lee R.
        • Malberg J.E.
        • Chen J.
        • Steffen C.
        • et al.
        Regulation of neurogenesis in adult mouse hippocampus by cAMP and the cAMP response element-binding protein.
        J Neurosci. 2002; 22: 3673-3682
        • Kodama M.
        • Fujioka T.
        • Duman R.S.
        Chronic olanzapine or fluoxetine administration increases cell proliferation in hippocampus and prefrontal cortex of adult rat.
        Biol Psychiatry. 2004; 56: 570-580
        • De Sarno P.
        • Li X.
        • Jope R.S.
        Regulation of Akt and glycogen synthase kinase-3β phosphorylation by sodium valproate and lithium.
        Neuropharmacology. 2002; 43: 1158-1164
        • Schmidt H.D.
        • Duman R.S.
        The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior.
        Behav Pharmacol. 2007; 18: 391-418
        • Kempermann G.
        • Krebs J.
        • Fabel K.
        The contribution of failing adult hippocampal neurogenesis to psychiatric disorders.
        Curr Opin Psychiatry. 2008; 21: 290-295
        • Mao Y.
        • Ge X.
        • Frank C.L.
        • et al.
        Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3β/β-catenin signaling.
        Cell. 2009; 136: 1017-1031
        • Mai L.
        • Jope R.S.
        • Li X.
        BDNF-mediated signal transduction is modulated by GSK3β and mood stabilizing agents.
        J Neurochem. 2002; 82: 75-83
        • Jin K.
        • Zhu Y.
        • Sun Y.
        • Mao X.O.
        • Xie L.
        • Greenberg D.A.
        Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo.
        Proc Natl Acad Sci U S A. 2002; 99: 11946-11950
        • Fabel K.
        • Fabel K.
        • Tam B.
        • Kaufer D.
        • Baiker A.
        • Simmons N.
        • et al.
        VEGF is necessary for exercise-induced adult hippocampal neurogenesis.
        Eur J Neurosci. 2003; 18: 2803-2812
        • Cao L.
        • Jiao X.
        • Zuzga D.S.
        • Liu Y.
        • Fong D.M.
        • Young D.
        • During M.J.
        VEGF links hippocampal activity with neurogenesis, learning and memory.
        Nat Genet. 2004; 36: 827-835
        • Miller B.H.
        • Schultz L.E.
        • Gulati A.
        • Cameron M.D.
        • Pletcher M.T.
        Genetic regulation of behavioral and neuronal responses to fluoxetine.
        Neuropsychopharmacology. 2008; 33: 1312-1322
        • Holick K.A.
        • Lee D.C.
        • Hen R.
        • Dulawa S.C.
        Behavioral effects of chronic fluoxetine in Balb/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor.
        Neuropsychopharmacology. 2008; 33: 406-417