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.

Epigenetic regulation of Dnmt3a and Arc gene expression after electroconvulsive stimulation in the rat

“…Indeed, it has been found that Hdac2 mRNA and protein levels increase after chronic ECS whereas acute ECS causes a non-significant upregulation (Park et al, 2014). Following chronic ECS, HDAC2 occupancy increased at the promoters of c-Fos and Egr1 with corresponding reductions in histone acetylation of H3 and/or H4 proteins (Park et al, 2014). This was correlated with decreased gene expression, which interestingly was ameliorated by the administration of sodium butyrate, a HDAC inhibitor, during the course of ECS.…”

“…A likely explanation is that the post-ECS Arc repression results from histone modifications. Indeed, it has been found that Hdac2 mRNA and protein levels increase after chronic ECS whereas acute ECS causes a non-significant upregulation (Park et al, 2014). Following chronic ECS, HDAC2 occupancy increased at the promoters of c-Fos and Egr1 with corresponding reductions in histone acetylation of H3 and/or H4 proteins (Park et al, 2014).…”

Can We Find Any Sustained Neurofunctional Alteration in Remitted Depressive Patients with a History of Modified Electroconvulsive Therapy?

“…It can be speculated that the functional difference between the left and right HPCs affected our results, as shown by the laterality of NMDA receptor distribution in the HPCs in a previous study (Goto et al, 2010). Since ECT is suggested to alter NMDA receptor (Park et al, 2014) and glutamate/glutamine expression levels (Michael et al, 2003), the asymmetric effects of ECT on neuronal HPC circuits associated with NMDA might occur after ECT. Further studies to reveal the pathophysiological mechanisms underlying the long-term effects of ECT on brain function are neces- There were several limitations in this study.…”

Epigenetics and Epilepsy

“…Other studies have reported PTM of histone variants following seizures in relation to DNA damage (Crowe et al 2011). Expression of HDAC2 is up-regulated in experimental and human epilepsy (Huang et al 2002(Huang et al , 2012, and predicted effects of changes in HDAC activity include transcriptional responses for several genes implicated in synaptic function, including ionotropic and metabotropic glutamate receptors (Huang et al 1999;Kurita et al 2012;Park et al 2014).…”