PT - JOURNAL ARTICLE AU - Mitsumasa Kurita AU - José L. Moreno AU - Terrell Holloway AU - Alexey Kozlenkov AU - Giuseppe Mocci AU - Aintzane García-Bea AU - James B. Hanks AU - Rachael Neve AU - Eric J. Nestler AU - Scott J. Russo AU - Javier González-Maeso TI - Repressive Epigenetic Changes at the <em>mGlu2</em> Promoter in Frontal Cortex of 5-HT<sub>2A</sub> Knockout Mice AID - 10.1124/mol.112.084582 DP - 2013 Jun 01 TA - Molecular Pharmacology PG - 1166--1175 VI - 83 IP - 6 4099 - http://molpharm.aspetjournals.org/content/83/6/1166.short 4100 - http://molpharm.aspetjournals.org/content/83/6/1166.full SO - Mol Pharmacol2013 Jun 01; 83 AB - 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.