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: 2.72). 05/2012; 88(5):507-13. DOI: 10.1016/j.brainresbull.2012.05.004
Source: PubMed


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.

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    • "As this study only investigates transcriptional changes, future experiments should be performed to investigate how these correlates with protein expression. We have previously (Dyrvig et al., 2012) measured c-Fos protein expression 10 min, 1 h, 4 h, 8 h, and 24 h after ECS and for this gene we observe the expected correlation. However, for the remaining genes it should be established if minor or inverse transcriptional changes are also evident at the protein level. "
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