Perinatal programming of neurodevelopment:lessons from a rat model of prenatal stress

ANTONELLI, MC

Munich

Seminario; Seminarios Científicos de la Unidad de Investigación Clinica; 2016

Departamento de Obstetricia y Ginecologia. Klinikum rechts der Isar. Technische. Universität Munchen.

The concept of ?developmental programming? was put forward in an attempt to explain the association between environmental challenges during pregnancy, altered foetal growth and development, and later pathophysiology. During programming, non-genetic factors such as stress or exposure to excess glucocorticoids, the main hormonal mediator of stress, are transmitted to the foetus and acts on specific tissues during sensitive windows of development to change developmental trajectories and thus their organisation and function. For the last fifteen years the focus of our research has been centered in the study of the outcome of various neurotransmitter pathways and hormones in a rodent model of prenatal restraint stress triggered by the hypothesis that stressful situations suffered prenatally are related to the propensity to develop psychiatric abnormalities in the human adult life. We observed an increase in the limbic area expression of dopamine (DA) receptors in offsprings of dams subjected to restrain stress (PS) during the last week of gestation. Adoption at birth was used to change the postnatal environment and the complex pattern of receptor changes obtained reflects the high vulnerability of DA system to variations both in prenatal and in postnatal environment. Behavioral studies have also been carried out and adult offsprings of rats stressed during pregnancy exhibited higher levels of anxiety than control rats. The anxiety levels show direct correlation with benzodiazepine receptors exhibiting a decrease in the number of benzodiazepine receptors (BDZ) binding sites in amygdala and hippocampus. We also performed morphological studies and found that PS induces a long-lasting astroglial reaction and a reduced dendritic arborization with synaptic loss in the brain of adult offsprings. Since many of the effects were only observed after puberty we postulated that the insult received prenatally might be modifying the sensitivity of the system to the modulation of sex steroids during puberty. In fact, we observed an impaired male offspring reproductive hormones profile and testis development. The disbalanced hormonal milieu might be responsible for the estrogen and dopamine receptors alterations and the impaired stress response in the adult offspring. Moreover, driven by the hypothesis that parental programming is mediated by epigenetic mechanisms that stably alter gene transcription affecting physiology and behavior, we analyzed the effect of PS on gpm6a expression and the epigenetic mechanism involved. gpm6a encodes the neuronal glycoprotein M6a involved in filopodium extension. We found that PS affected gpm6a gene expression in offspring likely through changes in methylation status and in posttranscriptional regulation by microRNAs. We are now developing a translational extense project with an international and multidisciplinary consortium aimed at exploring the feasibility of measuring biomarkers from cord blood, salivary and stool in newborns as a predictive marker of PS-induced epigenetic reprogramming.