Maternal Care Permanently Alters DNA Structure and thus Programs Gene Expression in Brain Regions That Regulate Stress Responses

MJ Meaney, ICG Weaver, M Szyf.
McGill Program for the Study of Behaviour, Genes and Environment,
Dept. of Psychiatry, Douglas Hospital Research Center,
McGill University, Montreal, Canada.

Variations in maternal in early postnatal life influence the development of individual differences in HPA responses to stress.  Specifically, the adult offspring of mothers that exhibit increased levels of pup licking/grooming (HIGH LG) show increased hippocampal glucocorticoid receptor expression, enhanced corticosteroid negative feedback sensitivity, decreased hypothalamic CRF, and dampened pituitary-adrenal responses to stress.  Maternal LG alters glucocorticoid receptor expression through a series of serotonin (5-HT) regulated pathways that involve the activation of cAMP/PKA signal transduction systems, with the subsequent increase NGFI-A expression.  NGFI-A binds to a consensus sequence on a neuron-specific promoter (exon 17 of the glucocorticoid receptor gene).  This consensus sequence has two CpG dinucleotides (5’ and 3’) and in adult offspring of Low LG mothers the 5’ CpG site is invariably methylated (on the cytosine), which blocks the ability of NGFI-A to interact with its consensus sequence and thus activate glucocorticoid receptor expression.  In the offspring of High LG mothers this same site is hypomethylated.  Chromiatin immunopreciptation assays confirm increased in vivo binding of NGFI-A to the exon 17 promoter in the adult offpsring of High LG mothers.  Methylation supresses gene expression through a series of protein-protein interactions that involve histone deactylase (HDAC).  When infused into the brain of the adult offspring of Low LG mothers, trichostatin A (TSA) an HDAC inhibitor, permits an increase in glucocorticoid receptor expression, presumably by removing the blockade of expression, and renders HPA responses to stress indistinguishable from the audlt offspring of High LG mothers.  These findings clarify a pathway that leads from maternal care to gene to function and, potentially, vulnerability/resistance to stress-induced illness.  

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