Maternal experience as a modulator of neurosteroid biosynthesis in the rat hippocampus

ROSSETTI MF; ANDREOLI MF; STOKER C; VARAYOUD J; LUQUE E H; RAMOS J G

Mendoza

Workshop; International Workshop in Neuroendocrinology; 2015

Pregnancy, lactation and maternal care has been shown to have a long-lasting impact on learning and memory abilities. In addition, some steroids synthesized in the brain have neurotrophic and neuroprotective properties. The purpose of the present study was to analyze the effects of reproductive experience on the age-related decline of mRNA expression of steroidogenic-related genes in the rat hippocampus, suggesting that differential DNA methylation mechanisms could be implicated.Female Wistar rats were divided into four groups: young nulliparous (YN); aged nulliparous (AN); aged multiparous subjected to three pregnancies with their respective lactation (MF+L) and aged multiparous subjected to three pregnancies without lactation (MF-L). Young and aged rats were sacrificed by decapitation at PND 90 or PND 450, respectively. The levels of mRNA and the DNA methylation state of genes involved in steroids synthesized were studied in the hippocampus. For mRNA analysis, reverse transcription and real-time quantitative PCR analysis were performed. The methylation state of gene promoters was studied using a combination of digestions with methylation-sensitive restriction enzymes and subsequent real-time PCR analysis. The mRNA expression of StAR, P450scc, 3beta-HSD, P450arom, P450(17alpha), 5alpha-reductase-1, 3alpha-HSD, P450(beta11)-2 and 17beta-HSD-3 decreased with progressive age (p < 0.05; YN vs AN). In adittion, a hypermethylation state at the P450scc and 5alpha-reductase-1 promoters was observed in aged compared with young rats. Interestingly, pregnancy and lactation increased the transcription of P450scc, 5alpha-reductase-1, P450arom and P450(11beta)-2 genes and decreased the methylation state of 5α-reductase-1 promoter in aged rats (p < 0.05; MF+L vs AN). Importantly, pregnancy itself (without lactation) is able to increased the transcription of P450scc and 5alpha-reductase-1 enzymes and reduced the methylation state of its promoters; however, a decreased in the mRNA levels of P450arom and P450 (beta11)-2 genes and an increased in the methylation state of P450arom promoter was found (p < 0.05; MF-L vs AN). In conclusions, aging decreases the transcription of steroidogenic enzymes and this is differentially attenuated by pregnancy and lactation in the rat hippocampus. Moreover, epigenetic mechanisms associated with differential promoter methylation could be involved. Thus, maternal experience could help to maintain adequate levels of neurosteroids in adulthood, pottentialy promoting hippocampal neuronal plasticity and preventing age-related neurodegenerative diseases.