, 2012). Additionally, in adult mice it was shown that stress responsivity in adulthood was correlated with methylation of the CRH promoter ( Elliott et al., 2010). The effects of PNS exposure on CRH DNA methylation remains to be
studied. Another candidate gene through which epigenetic mechanisms may affect the PNS associated phenotype is BDNF. Roth and colleagues showed that early postnatal stress increased DNA methylation of BDNF exon IV (Roth et al., 2011). We recently showed that prenatal stress also increased DNA methylation of both exons IV and VI of the BDNF gene (Boersma et al., Proteasome inhibition 2014b), implying that the decrease in expression of Bdnf in PNS offspring may be mediated by increased DNA methylation. The expression of the coding Bdnf exon IX has an inverted U-shape developmental pattern with peak levels between postnatal day P14 through P21, suggesting that this might be the critical period for BDNF action ( Das et al., 2001). Following this peak, Bdnf exon
IX expression levels decrease until P28 and then Bdnf exon IX expression levels remain stable through adulthood. Alterations in specific Bdnf exon expression may be important for neuronal development since the different Bdnf exons show different temporal expression patterns through development. Interestingly, the postnatal surge in BDNF protein seems to coincide with an increase in Bdnf exon IV expression suggesting that this exon might OTX015 nmr be important for BDNF levels during this period. Developmental patterns of expression of the specific Bdnf exons in response to PNS in brain regions important all for stress related behaviors have not been studied. Therefore the roles of
specific Bdnf exons in the neuronal development of those specific brain regions after PNS exposure needs further study. In addition to having direct effects on the exposed offspring, prenatal stress exposure may also have effects on subsequent generations. Although the mechanism by which epigenetic modifications are transmitted to the next generation is not fully understood, more evidence has arisen indicating that, at least for some imprinted genes, epigenetic profiles can be maintained or re-programmed in the progeny (Borgel et al., 2010). In mice, it was shown that the effects of early postnatal maternal separation on social and depression-like behaviors were transmitted to both the F2 and F3 generations (Franklin et al., 2010, Franklin et al., 2011 and Weiss et al., 2011). Roth and colleagues showed that alterations in Bdnf gene expression and DNA methylation in the prefrontal cortex associated with reduced maternal care were found in both the F1 and F2 generations concurrent with altered maternal behavior in daughters (F1) and granddaughters (F2). Thus, epigenetic signatures and associated behaviors may be transmitted over multiple generations ( Roth et al., 2009).