Maternal Care and DNA Methylation of a Glutamic Acid Decarboxylase 1 Promoter in Rat Hippocampus

Parenting and the early environment influence the risk for various psychopathologies. Studies in the rat suggest that variations in maternal care stably influence DNA methylation, gene expression, and neural function in the offspring. Maternal care affects neural development, including the GABAergic system, the function of which is linked to the pathophysiology of diseases including schizophrenia and depression. Postmortem studies of human schizophrenic brains have revealed decreased forebrain expression of glutamic acid decarboxylase 1 (GAD1) accompanied by increased methylation of aGAD1promoter. We examined whether maternal care affectsGAD1promoter methylation in the hippocampus of adult male offspring of high and low pup licking/grooming (high-LG and low-LG) mothers. Compared with the offspring of low-LG mothers, those reared by high-LG dams showed enhanced hippocampalGAD1mRNA expression, decreased cytosine methylation, and increased histone 3–lysine 9 acetylation (H3K9ac) of theGAD1promoter. DNA methyltransferase 1 expression was significantly higher in the offspring of low- compared with high-LG mothers. Pup LG increases hippocampal serotonin (5-HT) and nerve growth factor-inducible factor A (NGFI-A) expression. Chromatin immunoprecipitation assays revealed enhanced NGFI-A association with and H3K9ac of theGAD1promoter in the hippocampus of high-LG pups after a nursing bout. Treatment of hippocampal neuronal cultures with either 5-HT or an NGFI-A expression plasmid significantly increasedGAD1mRNA levels. The effect of 5-HT was blocked by a short interfering RNA targeting NGFI-A. These results suggest that maternal care influences the development of the GABA system by alteringGAD1promoter methylation levels through the maternally induced activation of NGFI-A and its association with theGAD1promoter.