26 February 2009. Childhood trauma, a risk factor for psychosis, blocks the functioning of a gene that keeps the human response to stress under check, according to research released online by Nature Neuroscience on February 22. The study, from a team that includes Michael Meaney of McGill University in Montreal, Quebec, extends prior observations that rat pups’ early life experiences may cause epigenetic changes. The new study suggests that being severely abused or neglected in childhood reduces expression of the glucocorticoid receptor gene in the hippocampus. It hints that adversity early in life induces lifelong changes in gene function that could increase the toll taken by stress and increase the likelihood of developing psychiatric disorders.
Normally, the hypothalamic-pituitary axis (HPA) helps organisms adapt to stress, which unleashes a cascade of events that tells the adrenal glands to release glucocorticoids. In humans, the glucocorticoid cortisol coordinates the stress response by binding to glucocorticoid and mineralocorticoid receptors on neurons and other cells. Through a negative feedback loop, the expression of glucocorticoid receptors in the hypothalamus dampens HPA reactivity to stress.
Individuals’ childhood experiences may shape their stress responses throughout life. For instance, rat pups with nurturing mothers that lick and groom them a lot show sustained decreases in HPA stress responses, an effect that Meaney’s group has linked to epigenetic factors that affect the expression of glucocorticoid receptors in the hippocampus (see Weaver et al., 2004; Weaver, 2009). In schizophrenia, adverse childhood experiences may intensify reactions to later hardships in life, thereby contributing to abnormalities in the hippocampus and other brain areas (see Walker et al., 2008; Lawrie et al., 2008; and see SRF related news story).
Meaney and colleagues, including first author Patrick McGowan, of the Douglas Mental Health University Institute in Montreal, note that severe childhood stress and psychiatric conditions associated with reduced expression of hippocampal glucocorticoid receptors seem to foster suicide. This, coupled with the prior findings from Meaney’s lab, led them to ask whether epigenetic processes might account for the effects of severe childhood stress on the brains of adult humans who commit suicide.
To address this issue, the researchers obtained samples of hippocampal tissue from the Quebec Suicide Brain Bank. All of the tissue came from male subjects: 12 suicide victims with a history of childhood abuse, 12 suicide victims with no such history, and 12 non-abused controls who died of other causes without receiving medical treatment. The abuse victims had suffered sexual abuse, severe physical abuse, or severe neglect.
McGowan and colleagues found less glucocorticoid receptor expression in the tissue from the abused suicide victims than in that from the other suicide victims or the control subjects. The same pattern emerged when they studied the expression of transcripts containing the exon 1F NR3C1 promoter, which regulates the expression of glucocorticoid receptors in human neurons. This promoter resembles the one in rats that showed epigenetic changes in response to the mother’s touch. Since the two groups of non-abused subjects showed similar expression levels, McGowan and colleagues attribute the expression differences to the abuse rather than other factors related to suicide.
Importantly, nucleotide sequences in the region of the NR3C1 promoter did not vary among groups. This suggests that the expression differences might stem from epigenetic factors rather than the genetic code itself.
One way that epigenetic changes occur is through the addition of a methyl group, or tag, to cytosine. This turns off the expression of the tagged gene (see SRF related news story; SRF news story). McGowan and colleagues found more of these tags in the abused suicide victims than in the other subjects, but only at specific sites in the NR3C1 promoter.
Previously, Meaney, Moshe Szyf at McGill University in Montreal, and their associates found that a transcription factor called nerve growth factor-inducible protein A (NGFI-A) controls expression of the Nr3c1 promoter in rats and that DNA methylation hinders this process (Weaver et al., 2007). In the new study, McGowan and colleagues report that a parallel process occurs in the human hippocampus, where NGFI-A normally starts transcription by binding with the exon 1F NR3C1 promoter. The methyl tags hamper its ability to do so.
Implications for schizophrenia
McGowan and colleagues conclude that childhood trauma correlates with altered glucocorticoid receptor expression in the hippocampus. They write, “It is tempting to speculate that epigenetic processes might mediate the effects of the social environment during childhood on hippocampal gene expression and that stable epigenetic marks such as DNA methylation might then persist into adulthood and influence the vulnerability for psychopathology through effects on intermediate levels of function, such as HPA activity.”
Speaking of psychopathology, the study could not tie mood disorders or substance abuse disorders to overall glucocorticoid receptor expression or to glucocorticoid receptor 1F expression. It did not specifically examine schizophrenia or psychosis. Whether childhood trauma actually causes psychosis remains controversial (see Read et al., 2005; Morgan and Fisher, 2007; Bendall et al., 2008). Even so, the possibility that such trauma leaves epigenetic scars on the brain offers plenty of fodder for future explorations of gene-environment interactions in schizophrenia.—Victoria L. Wilcox.
McGowan PO, Sasaki A, D’Alessio AC, Dymov S, Labonté B, Szyf M, Turecki G, Meaney MJ. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci. 2009 February 22. Abstract