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Research ArticleArticle

Activation of Group II Metabotropic Glutamate Receptors Promotes DNA Demethylation in the Mouse Brain

Francesco Matrisciano, Erbo Dong, David Peter Gavin, Ferdinando Nicoletti and Alessandro Guidotti
Molecular Pharmacology July 2011, 80 (1) 174-182; DOI: https://doi.org/10.1124/mol.110.070896
Francesco Matrisciano
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Erbo Dong
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David Peter Gavin
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Ferdinando Nicoletti
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Alessandro Guidotti
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Abstract

Activation of group II metabotropic glutamate receptors (mGlu2 and -3 receptors) has shown a potential antipsychotic activity, yet the underlying mechanism is only partially known. Altered epigenetic mechanisms contribute to the pathogenesis of schizophrenia and currently used medications exert chromatin remodeling effects. Here, we show that systemic injection of the brain-permeant mGlu2/3 receptor agonist (−)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268; 0.3–1 mg/kg i.p.) increased the mRNA and protein levels of growth arrest and DNA damage 45-β (Gadd45-β), a molecular player of DNA demethylation, in the mouse frontal cortex and hippocampus. Induction of Gadd45-β by LY379268 was abrogated by the mGlu2/3 receptor antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495; 1 mg/kg i.p.). Treatment with LY379268 also increased the amount of Gadd45-β bound to specific promoter regions of reelin, brain-derived neurotrophic factor (BDNF), and glutamate decarboxylase-67 (GAD67). We directly assessed gene promoter methylation in control mice and in mice pretreated for 7 days with the methylating agent methionine (750 mg/kg i.p.). Both single and repeated injections with LY379268 reduce cytosine methylation in the promoters of the three genes, although the effect on the GAD67 was significant only in response to repeated injections. Single and repeated treatment with LY379268 could also reverse the defect in social interaction seen in mice pretreated with methionine. The action of LY379268 on Gadd45-β was mimicked by valproate and clozapine but not haloperidol. These findings show that pharmacological activation of mGlu2/3 receptors has a strong impact on the epigenetic regulation of genes that have been linked to the pathophysiology of schizophrenia.

Footnotes

  • This work was supported in part by the National Institutes of Health National Institute of Mental Health [Grant MH070855].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.070896.

  • ABBREVIATIONS:

    mGlu
    metabotropic glutamate
    LY354740
    (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid
    SZ
    schizophrenia
    LY404039
    (−)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid
    VPA
    valproate
    Gadd45
    growth arrest and DNA-damage-inducible protein 45
    BDNF
    brain-derived neurotrophic factor
    LY379268
    (−)-2-Oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylic acid
    LY341495
    (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid
    VEH
    vehicle
    CLZ
    clozapine
    ChIP
    chromatin immunoprecipitation
    PCR
    polymerase chain reaction
    NSE
    neuron-specific enolase
    KO
    knockout
    PBS
    phosphate-buffered saline
    FC
    frontal cortex
    bp
    base pair(s)
    MeDIP
    5-methyl-cytosine DNA immunoprecipitation
    ANOVA
    analysis of variance
    HAL
    haloperidol.

  • Received January 10, 2011.
  • Accepted April 19, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (1)
Molecular Pharmacology
Vol. 80, Issue 1
1 Jul 2011
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Research ArticleArticle

Activation of Group II Metabotropic Glutamate Receptors Promotes DNA Demethylation in the Mouse Brain

Francesco Matrisciano, Erbo Dong, David Peter Gavin, Ferdinando Nicoletti and Alessandro Guidotti
Molecular Pharmacology July 1, 2011, 80 (1) 174-182; DOI: https://doi.org/10.1124/mol.110.070896

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Research ArticleArticle

Activation of Group II Metabotropic Glutamate Receptors Promotes DNA Demethylation in the Mouse Brain

Francesco Matrisciano, Erbo Dong, David Peter Gavin, Ferdinando Nicoletti and Alessandro Guidotti
Molecular Pharmacology July 1, 2011, 80 (1) 174-182; DOI: https://doi.org/10.1124/mol.110.070896
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