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The Journal of Neuroscience, June 16, 2004, 24(24):5603-5610; doi:10.1523/JNEUROSCI.0589-04.2004

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Development/Plasticity/Repair
Histone Modifications at Gene Promoter Regions in Rat Hippocampus after Acute and Chronic Electroconvulsive Seizures

Nadia M. Tsankova, Arvind Kumar, and Eric J. Nestler

Department of Psychiatry and Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070

The mechanism of action of electroconvulsive seizures (ECS), one of the most effective treatments of major depression, may involve the regulation of gene expression. Chromatin remodeling at gene promoter regions is increasingly recognized as a key control point of gene expression and may, therefore, partly mediate acute and chronic effects of ECS on gene activity. Here, we assayed how posttranslational modifications of histones, a major form of chromatin remodeling, are altered at several gene promoters in rat hippocampus at 30 min, 2 hr, and 24 hr after acute or repeated ECS. We performed chromatin immunoprecipitation assays to measure levels of histone H3 and H4 acetylation and phosphoacetylation at the promoters of the c-fos, BDNF, and CREB (cAMP response element-binding protein) genes, the expression of which is altered by ECS. We found that, with few exceptions, levels of H4 acetylation correlated with mRNA levels for c-fos, BDNF, and CREB throughout the acute and chronic time course study, whereas acetylation and phosphoacetylation of H3 were detected more selectively. Our findings suggest that the chronic downregulation of c-fos transcription, observed in this study, may be achieved at the level of H4 acetylation, whereas chronic upregulation of BDNF transcription may be sustained via control of H3 acetylation, selectively at the BDNF P3 and P4 promoters. These data provide the first in vivo demonstration of the involvement of chromatin remodeling in ECS-induced regulation of gene expression in the brain and will help in understanding the mechanisms underlying the efficacy of ECS in the treatment of depression.

Key words: chromatin remodeling; histones; electroconvulsive seizure; gene regulation; hippocampus; depression

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Received Feb 18, 2004; revised May 4, 2004; accepted May 11, 2004.

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