title: HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity.
abstract: Histone deacetylases (HDACs) compact chromatin structure and repress gene transcription. In schizophrenia, clinical studies demonstrate that HDAC inhibitors are efficacious when given in combination with atypical antipsychotics. However, the molecular mechanism that integrates a better response to antipsychotics with changes in chromatin structure remains unknown. Here we found that chronic atypical antipsychotics downregulated the transcription of metabotropic glutamate 2 receptor (mGlu2, also known as Grm2), an effect that was associated with decreased histone acetylation at its promoter in mouse and human frontal cortex. This epigenetic change occurred in concert with a serotonin 5-HT(2A) receptor-dependent upregulation and increased binding of HDAC2 to the mGlu2 promoter. Virally mediated overexpression of HDAC2 in frontal cortex decreased mGlu2 transcription and its electrophysiological properties, thereby increasing psychosis-like behavior. Conversely, HDAC inhibitors prevented the repressive histone modifications induced at the mGlu2 promoter by atypical antipsychotics, and augmented their therapeutic-like effects. These observations support the view of HDAC2 as a promising new target for schizophrenia treatment.
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Mitsumasa
authors.initials: M
authors.lastname: Kurita
authors.forename: Terrell
authors.initials: T
authors.lastname: Holloway
authors.forename: Aintzane
authors.initials: A
authors.lastname: García-Bea
authors.forename: Alexey
authors.initials: A
authors.lastname: Kozlenkov
authors.forename: Allyson K
authors.initials: AK
authors.lastname: Friedman
authors.forename: José L
authors.initials: JL
authors.lastname: Moreno
authors.forename: Mitra
authors.initials: M
authors.lastname: Heshmati
authors.forename: Sam A
authors.initials: SA
authors.lastname: Golden
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Kennedy
authors.forename: Nagahide
authors.initials: N
authors.lastname: Takahashi
authors.forename: David M
authors.initials: DM
authors.lastname: Dietz
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mocci
authors.forename: Ane M
authors.initials: AM
authors.lastname: Gabilondo
authors.forename: James
authors.initials: J
authors.lastname: Hanks
authors.forename: Adrienne
authors.initials: A
authors.lastname: Umali
authors.forename: Luis F
authors.initials: LF
authors.lastname: Callado
authors.forename: Amelia L
authors.initials: AL
authors.lastname: Gallitano
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: Ming-Hu
authors.initials: MH
authors.lastname: Han
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
authors.forename: J Javier
authors.initials: JJ
authors.lastname: Meana
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Russo
authors.forename: Javier
authors.initials: J
authors.lastname: González-Maeso
mesh_terms: D000107:Acetylation; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D047369:Chromatin Immunoprecipitation; D003024:Clozapine / Q000494:pharmacology; D019175:DNA Methylation; D005822:Genetic Vectors; D057809:HEK293 Cells; D018258:Herpesvirus 2, Human / Q000235:genetics; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D006657:Histones / Q000378:metabolism / Q000502:physiology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D010957:Plasmids / Q000235:genetics; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects / Q000235:genetics; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000502:physiology*; D013216:Reflex, Startle / Q000502:physiology; D012565:Schizophrenic Psychology; D000077337:Vorinostat
chemical_list: D014150:Antipsychotic Agents; D001549:Benzamides; D006657:Histones; D006877:Hydroxamic Acids; D011725:Pyridines; D044402:Receptor, Serotonin, 5-HT2A; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C118739:entinostat; D000077337:Vorinostat; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2; D003024:Clozapine