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The Journal of Neuroscience, November 23, 2005, 25(47):11045-11054; doi:10.1523/JNEUROSCI.3652-05.2005

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Development/Plasticity/Repair
Reversal of Maternal Programming of Stress Responses in Adult Offspring through Methyl Supplementation: Altering Epigenetic Marking Later in Life

Ian C. G. Weaver,^1,2 Frances A. Champagne,¹ Shelley E. Brown,³ Sergiy Dymov,³ Shakti Sharma,¹ Michael J. Meaney,^1,2 and Moshe Szyf^2,3

¹Douglas Hospital Research Center, Montréal, Québec H4H 1R3, Canada, and ²McGill Program for the Study of Behaviour, Genes, and Environment and ³Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec H3G 1Y6, Canada

Stress responses in the adult rat are programmed early in life by maternal care and associated with epigenomic marking of the hippocampal exon 1₇ glucocorticoid receptor (GR) promoter. To examine whether such epigenetic programming is reversible in adult life, we centrally infused the adult offspring with the essential amino acid L-methionine, a precursor to S-adenosyl-methionine that serves as the donor of methyl groups for DNA methylation. Here we report that methionine infusion reverses the effect of maternal behavior on DNA methylation, nerve growth factor-inducible protein-A binding to the exon 1₇ promoter, GR expression, and hypothalamic-pituitary-adrenal and behavioral responses to stress, suggesting a causal relationship among epigenomic state, GR expression, and stress responses in the adult offspring. These results demonstrate that, despite the inherent stability of the epigenomic marks established early in life through behavioral programming, they are potentially reversible in the adult brain.

Key words: maternal behavior; rat; hippocampus; glucocorticoid receptor; epigenetics; L-methionine

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Received Aug 28, 2005; revised October 12, 2005; accepted October 12, 2005.

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