Article

Epigenetic regulation of Arc and c-Fos in the hippocampus after acute electroconvulsive stimulation in the rat

Laboratory of Neurobiology, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark.
Brain research bulletin (Impact Factor: 2.97). 05/2012; 88(5):507-13. DOI: 10.1016/j.brainresbull.2012.05.004
Source: PubMed

ABSTRACT Electroconvulsive stimulation (ECS) remains one of the most effective treatments of major depression. However, the underlying molecular changes still remain to be elucidated. Since ECS causes rapid and significant changes in gene expression we have looked at epigenetic regulation of two important immediate early genes that are both induced after ECS: c-Fos and Arc. We examined Arc and c-Fos protein expression and found Arc present over 4 h, in contrast to c-Fos presence lasting only 1 h. Both genes had returned to baseline expression at 24 h post-ECS. Histone H4 acetylation (H4Ac) is one of the important epigenetic marks associated with gene activation. We show increased H4Ac at the c-Fos promoter at 1 h post-ECS. Surprisingly, we also observed a significant increase in DNA methylation of the Arc gene promoter at 24 h post-ECS. DNA methylation, which is responsible for gene silencing, is a rather stable covalent modification. This suggests that Arc expression has been repressed and may consequently remain inhibited for a prolonged period post-ECS. Arc plays a critical role in the maintenance phase of long-term potentiation (LTP) and consolidation of memory in the rat brain. Thus, this study is one of the first to demonstrate DNA methylation as a regulator of ECS-induced gene expression and it provides a molecular link to the memory deficits observed after ECS.

0 Followers
 · 
137 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Fetal and subsequent early postnatal iron deficiency causes persistent impairments in cognitive and affective behaviors despite prompt postnatal iron repletion. The long-term cognitive impacts are accompanied by persistent downregulation of brain-derived neurotrophic factor (BDNF), a factor critical for hippocampal plasticity across the life span. This study determined whether early-life iron deficiency epigenetically modifies the Bdnf locus and whether dietary choline supplementation during late gestation reverses these modifications. DNA methylation and histone modifications were assessed at the Bdnf-IV promoter in postnatal day (PND) 65 hippocampus of rats that were iron-deficient (ID) during the fetal-neonatal period. Iron deficiency was induced in rat pups by providing pregnant and nursing dams an ID diet (4 mg/kg Fe) from gestational day (G) 2 through PND7, after which iron deficiency was treated with an iron-sufficient (IS) diet (200 mg/kg Fe). This paradigm resulted in about 60% hippocampal iron loss on PND15 with complete recovery by PND65. For choline supplementation, pregnant rat dams were given dietary choline (5 g/kg) from G11 through G18. DNA methylation was determined by quantitative sequencing of bisulfite-treated DNA, revealing a small alteration at the Bdnf-IV promoter. Chromatin immunoprecipitation analysis showed increased HDAC1 binding accompanied by reduced binding of RNA polymerase II and USF1 at the Bdnf-IV promoter in formerly ID rats. These changes were correlated with altered histone methylations. Prenatal choline supplementation reverses these epigenetic modifications. Collectively, the findings identify epigenetic modifications as a potential mechanism to explicate the long-term repression of Bdnf following fetal and early postnatal iron deficiency. Copyright © 2014, American Journal of Physiology - Regulatory, Integrative and Comparative Physiology.
    AJP Regulatory Integrative and Comparative Physiology 12/2014; 308(4):ajpregu.00429.2014. DOI:10.1152/ajpregu.00429.2014 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although multipotent cell types have enlarged nuclei with decondensed chromatin, this property has not been exploited to enhance the characterization of neural progenitor cell (NPC) populations in the brain. We found that mouse brain cell nuclei that expressed exceptionally high levels of the pan neuronal marker NeuN/FOX3 (NeuN-High) had decondensed chromatin relative to most NeuN-Low or NeuN-Neg (negative) nuclei. Purified NeuN-High nuclei expressed significantly higher levels of transcripts encoding markers of neurogenesis, neuroplasticity, and learning and memory (ARC, BDNF, ERG1, HOMER1, NFL/NEF1, SYT1), subunits of chromatin modifying machinery (SIRT1, HDAC1, HDAC2, HDAC11, KAT2B, KAT3A, KAT3B, KAT5, DMNT1, DNMT3A, Gadd45a, Gadd45b) and markers of neural progenitor cell and cell cycle activity (BRN2, FOXG1, KLF4, c-MYC, OCT4, PCNA, SHH, Sox2) relative to neuronal NeuN-Low or to mostly non-neuronal NeuN-Neg nuclei. NeuN-High nuclei expressed higher levels of HDAC1, 2, 4, and 5 proteins. The cortex, hippocampus, hypothalamus, thalamus, and nucleus accumbens contained high percentages of large decondensed NeuN-High nuclei, while the cerebellum, and pons contained very few. NeuN-High nuclei have the properties consistent with their being derived from extremely active neurons with elevated rates of chromatin modification and/or NPC-like cells with multi-lineage developmental potential. The further analysis of decondensed neural cell nuclei should provide novel insights into neurobiology and neurodegenerative disease. © 2014 Wiley Periodicals, Inc. Develop Neurobiol, 2014
    Developmental Neurobiology 11/2014; DOI:10.1002/dneu.22245 · 4.19 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hypoxia is a major stress to the fetal development and may result in irreversible injury in the developing brain, increased risk of central nervous system (CNS) malformations in the neonatal brain and long-term neurological complications in offspring. Current evidence indicates that epigenetic mechanisms may contribute to the development of hypoxic/ischemic-sensitive phenotype in the developing brain in response to fetal stress. However, the causative cellular and molecular mechanisms remain elusive. In the present review, we summarize the recent findings of epigenetic mechanisms in the development of the brain and their roles in fetal hypoxia-induced brain developmental malformations. Specifically, we focus on DNA methylation and active demethylation, histone modifications and microRNAs in the regulation of neuronal and vascular developmental plasticity, which may play a role in fetal stress-induced epigenetic programming of hypoxic/ischemic-sensitive phenotype in the developing brain. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Progress in Neurobiology 11/2014; DOI:10.1016/j.pneurobio.2014.11.001 · 10.30 Impact Factor

Full-text

Download
74 Downloads
Available from
May 23, 2014