Abstract
Background
Exposure to early life stress (ELS) represents a major risk factor for the development of psychiatric disorders, including depression and schizophrenia. The susceptibility associated with ELS may result from persistent changes in gene transcription, which can occur through epigenetic mechanisms, such as DNA methylation and miRNA expression. Animal models are particularly useful to identify the systems that are persistently affected as a consequence of ELS exposure and that may represent suitable targets for pharmacological intervention. On these bases, we performed genome-wide methylation analyses in rats exposed to gestational stress, a model associated with functional alterations relevant for psychiatric disorders, in order to identify systems that are persistently altered as a consequence of the adverse experience early in life.
Methods
We used MeDIP-chip to investigate changes in the prefrontal cortex and hippocampus of adult male and female rats exposed to chronic stress (immobilization under bright light) during the last week of gestation (PNS). After having identified the most promising candidates from this analysis, we investigated their expression profile during postnatal maturation, in order to establish potential changes in their developmental trajectories. We also investigated whether sub-chronic treatment with the antipsychotic drug lurasidone, given during the peripubertal period, could modulate the changes originating from PNS exposure.
Results
We found that a large number of gene promoters were differentially methylated in the prefrontal cortex and hippocampus of adult male and female rats exposed to stress during gestation. An overlap of 138 differentially methylated genes around the transcription start site was observed among the two brain regions and genders. By restricting the overlap to genes that were modulated in the same direction, we identified two genes, miR-30a and NEUROD1, which interact with each other and that were both less methylated in PNS exposed rats. Using the miRWalk database, we found that miRNA30a is involved in the modulation of pathways related to axon guidance and neurotrophin signaling. Among the genes related to these two pathways, we validated CAMK2A, c-JUN, LIMK, MAP2K1, MAP2K2, PIK3CA and PLCG1 as miRNA30 targeted genes. We found that the cumulative score of their mRNA level modulation following PNS exposure supported the downregulation of the two identified pathways related to miRNA30a. Importantly, sub-chronic treatment with lurasidone was able to prevent, to a large extent, the up-regulation of miR30a, as well as the changes observed on its target genes
Discussion
In summary, our genome-wide approach allowed us to identify miR-30a as being persistently affected by PNS through epigenetic changes. This miRNA may represent a master regulator for the increased susceptibility to psychiatric disorders as a long-lasting consequence of ELS exposure. Furthermore, we show that chronic lurasidone treatment was able to prevent some of the changes produced by PNS, with a major effect on miRNA30a levels as well as on its target genes LIMK, MAP2K2 and PIK3CA.
These effects may be particularly relevant in preventing some molecular alterations induced by ELS exposure, known to be involved in the development of stress-related psychiatric disorders, and thus be useful in minimizing the individual risk of vulnerability.
Perinatal Exposure to an Environmentally Relevant Mixture of Phthalates Results in a Lower Number of Neurons and Synapses in the Medial Prefrontal Cortex and Decreased Cognitive Flexibility in Adult Male and Female Rats
