TY - JOUR T1 - Repressive Epigenetic Changes at the Mglu2 Promoter in Frontal Cortex of 5-HT2A Knockout Mice JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.112.084582 SP - mol.112.084582 AU - Mitsumasa Kurita AU - Jose L Moreno AU - Terrell Holloway AU - Alexey Kozlenkov AU - Giuseppe Mocci AU - Aintzane Garcia-Bea AU - James B Hanks AU - Rachael Neve AU - Eric J Nestler AU - Scott J Russo AU - Javier Gonzalez-Maeso Y1 - 2013/01/01 UR - http://molpharm.aspetjournals.org/content/early/2013/03/18/mol.112.084582.abstract N2 - 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 whose promoter activity was positively regulated by the 5-HT2A receptor agonist TCB-2, binds less to the mGlu2 promoter in frontal cortex of 5-HT2A-KO as compared to 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. ER -