Epigenetic signatures of early life adversities in animal models: A role for psychopathology vulnerability

Abstract

Stressful experiences early in life (ELS) represent one of the most relevant factors for the vulnerability to psychopathologies. Epigenetic changes, such as DNA methylation, have emerged as a major mechanism through which ELS can alter adult behaviour leading to persistent changes of gene regulation.We performed DNA methylation analyses in the hippocampus and prefrontal cortex of adult rats exposed to stress during gestation (PNS), a model that is associated with persistent behavioral alterations relevant for psychiatric disorders.Using an epigenome-wide analysis, an overlap of 893 differentially methylated genes was observed between hippocampus and prefrontal cortex of adult male and female rats exposed to PNS. The list includes several genes previously associated with schizophrenia and other psychiatric conditions, such as calcium and potassium voltage operated channels as well as GABA and glutamate receptor subunits. By restricting the overlap to genes that were modulated in the same direction, we identified miR-30a as being less methylated in PNS rats. Interestingly one of the targets for this miRNA is the neurotrophin BDNF, whose expression was indeed reduced as a consequence of the prenatal manipulation. Interestingly chronic treatment of PNS rats with the multi-receptor modulator lurasidone during adolescence was able to prevent the changes in miR30a and BDNF expression.These results highlight the importance for the identification of methylation signatures through which stress exposure early in life could engrave on the outcome of the adult phenotype, and may allow the identification of novel genes and pathways that are affected as a consequence of ELS.Disclosure of interestM.A.R. has received compensation as speaker/consultant from Lundbeck, Otzuka, Sumitomo Dainippon Pharma and Sunovion. He has received research grants from Lundbeck, Sumitomo Dainippon Pharma and Sunovion.