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Research ArticleArticle

Repressive Epigenetic Changes at the mGlu2 Promoter in Frontal Cortex of 5-HT2A Knockout Mice

Mitsumasa Kurita, José L. Moreno, Terrell Holloway, Alexey Kozlenkov, Giuseppe Mocci, Aintzane García-Bea, James B. Hanks, Rachael Neve, Eric J. Nestler, Scott J. Russo and Javier González-Maeso
Molecular Pharmacology June 2013, 83 (6) 1166-1175; DOI: https://doi.org/10.1124/mol.112.084582
Mitsumasa Kurita
Departments of Psychiatry (M.K., J.L.M., T.H., A.K., G.M., A.G.B., J.B.H., E.J.N., J.G.M.), Neurology (J.G.M.), Neuroscience (E.J.N., S.J.C.), Pharmacology and Systems Therapeutics (E.J.N.), and Friedman Brain Institute (E.J.N., S.J.R., J.G.M.), Icahn School of Medicine at Mount Sinai, New York, New York; and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts (R.N.)
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José L. Moreno
Departments of Psychiatry (M.K., J.L.M., T.H., A.K., G.M., A.G.B., J.B.H., E.J.N., J.G.M.), Neurology (J.G.M.), Neuroscience (E.J.N., S.J.C.), Pharmacology and Systems Therapeutics (E.J.N.), and Friedman Brain Institute (E.J.N., S.J.R., J.G.M.), Icahn School of Medicine at Mount Sinai, New York, New York; and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts (R.N.)
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Terrell Holloway
Departments of Psychiatry (M.K., J.L.M., T.H., A.K., G.M., A.G.B., J.B.H., E.J.N., J.G.M.), Neurology (J.G.M.), Neuroscience (E.J.N., S.J.C.), Pharmacology and Systems Therapeutics (E.J.N.), and Friedman Brain Institute (E.J.N., S.J.R., J.G.M.), Icahn School of Medicine at Mount Sinai, New York, New York; and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts (R.N.)
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Alexey Kozlenkov
Departments of Psychiatry (M.K., J.L.M., T.H., A.K., G.M., A.G.B., J.B.H., E.J.N., J.G.M.), Neurology (J.G.M.), Neuroscience (E.J.N., S.J.C.), Pharmacology and Systems Therapeutics (E.J.N.), and Friedman Brain Institute (E.J.N., S.J.R., J.G.M.), Icahn School of Medicine at Mount Sinai, New York, New York; and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts (R.N.)
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Giuseppe Mocci
Departments of Psychiatry (M.K., J.L.M., T.H., A.K., G.M., A.G.B., J.B.H., E.J.N., J.G.M.), Neurology (J.G.M.), Neuroscience (E.J.N., S.J.C.), Pharmacology and Systems Therapeutics (E.J.N.), and Friedman Brain Institute (E.J.N., S.J.R., J.G.M.), Icahn School of Medicine at Mount Sinai, New York, New York; and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts (R.N.)
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Aintzane García-Bea
Departments of Psychiatry (M.K., J.L.M., T.H., A.K., G.M., A.G.B., J.B.H., E.J.N., J.G.M.), Neurology (J.G.M.), Neuroscience (E.J.N., S.J.C.), Pharmacology and Systems Therapeutics (E.J.N.), and Friedman Brain Institute (E.J.N., S.J.R., J.G.M.), Icahn School of Medicine at Mount Sinai, New York, New York; and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts (R.N.)
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James B. Hanks
Departments of Psychiatry (M.K., J.L.M., T.H., A.K., G.M., A.G.B., J.B.H., E.J.N., J.G.M.), Neurology (J.G.M.), Neuroscience (E.J.N., S.J.C.), Pharmacology and Systems Therapeutics (E.J.N.), and Friedman Brain Institute (E.J.N., S.J.R., J.G.M.), Icahn School of Medicine at Mount Sinai, New York, New York; and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts (R.N.)
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Rachael Neve
Departments of Psychiatry (M.K., J.L.M., T.H., A.K., G.M., A.G.B., J.B.H., E.J.N., J.G.M.), Neurology (J.G.M.), Neuroscience (E.J.N., S.J.C.), Pharmacology and Systems Therapeutics (E.J.N.), and Friedman Brain Institute (E.J.N., S.J.R., J.G.M.), Icahn School of Medicine at Mount Sinai, New York, New York; and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts (R.N.)
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Eric J. Nestler
Departments of Psychiatry (M.K., J.L.M., T.H., A.K., G.M., A.G.B., J.B.H., E.J.N., J.G.M.), Neurology (J.G.M.), Neuroscience (E.J.N., S.J.C.), Pharmacology and Systems Therapeutics (E.J.N.), and Friedman Brain Institute (E.J.N., S.J.R., J.G.M.), Icahn School of Medicine at Mount Sinai, New York, New York; and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts (R.N.)
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Scott J. Russo
Departments of Psychiatry (M.K., J.L.M., T.H., A.K., G.M., A.G.B., J.B.H., E.J.N., J.G.M.), Neurology (J.G.M.), Neuroscience (E.J.N., S.J.C.), Pharmacology and Systems Therapeutics (E.J.N.), and Friedman Brain Institute (E.J.N., S.J.R., J.G.M.), Icahn School of Medicine at Mount Sinai, New York, New York; and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts (R.N.)
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Javier González-Maeso
Departments of Psychiatry (M.K., J.L.M., T.H., A.K., G.M., A.G.B., J.B.H., E.J.N., J.G.M.), Neurology (J.G.M.), Neuroscience (E.J.N., S.J.C.), Pharmacology and Systems Therapeutics (E.J.N.), and Friedman Brain Institute (E.J.N., S.J.R., J.G.M.), Icahn School of Medicine at Mount Sinai, New York, New York; and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts (R.N.)
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Abstract

Serotonin 5-HT2A and metabotropic glutamate 2 (mGlu2) are G protein–coupled receptors suspected in the pathophysiology of psychiatric disorders, such as schizophrenia, depression, and suicide. Previous findings demonstrate that mGlu2 mRNA expression is down-regulated in brain cortical regions of 5-HT2A knockout (KO) mice. However, the molecular mechanism responsible for this alteration remains unknown. We show here repressive epigenetic changes at the promoter region of the mGlu2 gene in frontal cortex of 5-HT2A-KO mice. Disruption of 5-HT2A receptor-dependent signaling in mice was associated with decreased acetylation of histone H3 (H3ac) and H4 (H4ac) and increased tri-methylation of histone H3 at lysine 27 (H3K27me3) at the mGlu2 promoter, epigenetic changes that correlate with transcriptional repression. Neither methylation of histone H3 at lysine 4 (H3K4me1/2/3) nor tri-methylation of histone H3 at lysine 9 (H3K9me3) was affected. We found that Egr1, a transcription factor in which promoter activity was positively regulated by the 5-HT2A receptor agonist 4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide, binds less to the mGlu2 promoter in frontal cortex of 5-HT2A-KO, compared with wild-type mice. Furthermore, expression of mGlu2 was increased by viral-mediated gene transfer of FLAG-tagged Egr1 in mouse frontal cortex. Together, these observations suggest that 5-HT2A receptor–dependent signaling epigenetically affects mGlu2 transcription in mouse frontal cortex.

Footnotes

    • Received December 19, 2012.
    • Accepted March 18, 2013.
  • ↵1 Current affiliation: Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan.

  • The work was funded by the National Institutes of Health [Grant MH084894]; Dainippon Sumitomo Pharma; the Brain & Behavior Research Foundation (NARSAD); the Maltz Family Foundation; Consejo Superior de Investigaciones Científicas (CSIC); and the Basque Government.

  • M.K. and J.L.M. contributed equally to this work.

  • dx.doi.org/10.1124/mol.112.084582.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 83 (6)
Molecular Pharmacology
Vol. 83, Issue 6
1 Jun 2013
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Research ArticleArticle

Epigenetic Changes at mGlu2 in 5-HT2A-KO Mice

Mitsumasa Kurita, José L. Moreno, Terrell Holloway, Alexey Kozlenkov, Giuseppe Mocci, Aintzane García-Bea, James B. Hanks, Rachael Neve, Eric J. Nestler, Scott J. Russo and Javier González-Maeso
Molecular Pharmacology June 1, 2013, 83 (6) 1166-1175; DOI: https://doi.org/10.1124/mol.112.084582

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Research ArticleArticle

Epigenetic Changes at mGlu2 in 5-HT2A-KO Mice

Mitsumasa Kurita, José L. Moreno, Terrell Holloway, Alexey Kozlenkov, Giuseppe Mocci, Aintzane García-Bea, James B. Hanks, Rachael Neve, Eric J. Nestler, Scott J. Russo and Javier González-Maeso
Molecular Pharmacology June 1, 2013, 83 (6) 1166-1175; DOI: https://doi.org/10.1124/mol.112.084582
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