ic regulation of the glucocorticoid receptor in human brain associates with childhood abuse.pdf

ARTICLES
ic regulation of the glucocorticoid receptor
in human brain associates with childhood abuse
Patrick O McGowan1,2, Aya Sasaki1,2, Ana C D’Alessio3, Sergiy Dymov3, Benoit Labonte´1,4, Moshe Szyf2,3,
Gustavo Turecki1,4 & Michael J Meaney1,2,5
Maternal care influences hypothalamic-pituitary-adrenal (HPA) function in the rat through ic programming of
glucocorticoid receptor expression. In humans, childhood abuse alters HPA stress responses and increases the risk of suicide.
We examined ic differences in a neuron-specific glucocorticoid receptor (NR3C1) promoter between postmortem
hippocampus obtained from suicide victims with a history of childhood abuse and those from either suicide victims with no
childhood abuse or controls. We found decreased levels of glucocorticoid receptor mRNA, as well as mRNA transcripts bearing the
glucocorticoid receptor 1F splice variant and increased cytosine methylation of an NR3C1 promoter. Patch-methylated NR3C1
promoter constructs that mimicked the methylation state in samples from abused suicide victims showed decreased NGFI-A
transcription factor binding and NGFI-A–inducible gene transcription. These findings translate previous results from rat to humans
and suggest mon effect of parental care on the ic regulation of hippocampal glucocorticoid receptor expression.
4,17
There are maternal effects on the developme