title: Repeated treatment with electroconvulsive seizures induces HDAC2 expression and down-regulation of NMDA receptor-related genes through histone deacetylation in the rat frontal cortex.
abstract: The enzymatic activity of histone deacetylases (HDACs) leads to a histone deacetylation-mediated condensed chromatic structure, resulting in transcriptional repression, which has been implicated in the modifications of neural circuits and behaviors. Repeated treatment with electroconvulsive seizure (ECS) induces changes in histone acetylation, expression of various genes, and intrabrain cellular changes, including neurogenesis. In this study, we examined the effects of repeated ECS on the expression of class I HDACs and related changes in histone modifications and gene expression in the rat frontal cortex. Ten days of repeated ECS treatments (E10X) up-regulated HDAC2 expression at the mRNA and protein levels in the rat frontal cortex compared with sham-treated controls; this was evident in the nuclei of neuronal cells in the prefrontal, cingulate, orbital, and insular cortices. Among the known HDAC2 target genes, mRNA expression of N-methyl-d-aspartate (NMDA) receptor signaling-related genes, including early growth response-1 (Egr1), c-Fos, glutamate receptor, ionotropic, N-methyl d-aspartate 2A (Nr2a), Nr2b, neuritin1 (Nrn1), and calcium/calmodulin-dependent protein kinase II alpha (Camk2α), were decreased, and the histone acetylation of H3 and/or H4 proteins was also reduced by E10X. Chromatin immunoprecipitation analysis revealed that HDAC2 occupancy in the promoters of down-regulated genes was increased significantly. Moreover, administration of sodium butyrate, a HDAC inhibitor, during the course of E10X ameliorated the ECS-induced down-regulation of genes in the rat frontal cortex. These findings suggest that induction of HDAC2 by repeated ECS treatment could play an important role in the down-regulation of NMDA receptor signaling-related genes in the rat frontal cortex through histone modification.
authors.affiliation: Biomedical Research Institute, Seoul National University Hospital,Seoul,Republic of Korea.
authors.forename: Hong Geun
authors.initials: HG
authors.lastname: Park
authors.affiliation: Biomedical Research Institute, Seoul National University Hospital,Seoul,Republic of Korea.
authors.forename: Hyun Sook
authors.initials: HS
authors.lastname: Yu
authors.affiliation: Biomedical Research Institute, Seoul National University Hospital,Seoul,Republic of Korea.
authors.forename: Soyoung
authors.initials: S
authors.lastname: Park
authors.affiliation: Biomedical Research Institute, Seoul National University Hospital,Seoul,Republic of Korea.
authors.forename: Yong Min
authors.initials: YM
authors.lastname: Ahn
authors.affiliation: Department of Neuropsychiatry,Dongguk University International Hospital, Dongguk University Medical School,Goyang-si, Gyeonggi-do,Republic of Korea.
authors.forename: Yong Sik
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Biomedical Research Institute, Seoul National University Hospital,Seoul,Republic of Korea.
authors.forename: Se Hyun
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D020148:Butyric Acid / Q000627:therapeutic use; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D004597:Electroshock / Q000009:adverse effects*; D005625:Frontal Lobe / Q000187:drug effects / Q000201:enzymology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006633:Histamine Antagonists / Q000627:therapeutic use; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D008297:Male; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012640:Seizures / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D005904:Glial Fibrillary Acidic Protein; D006633:Histamine Antagonists; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D020148:Butyric Acid; C533426:Hdac2 protein, rat; D056464:Histone Deacetylase 2; D010751:Phosphopyruvate Hydratase