Activity-dependent Signaling and Epigenetic Abnormalities in Mice Exposed to Postnatal Ethanol

Postnatal ethanol exposure causes activity dependent signaling defects and epigenetic abnormalities in adult mice and CB1R antagonist or G9a/GLP inhibitor rescues these defects. Y-maze spatial memory behavior was used as activity-dependent event and current findings suggest that P7 ethanol treatment impair activity-dependent recruitment of CBP and G9a on Arc gene promoter region, inhibit Arc expression and CB1R antagonist (SR) and/or G9a/GLP inhibitor (Bix) rescue these signaling and epigenetic remodeling and Arc expression. [Display omitted] •Postnatal ethanol treatment impairs spatial memory behavior on Y-maze in adult mice.•Ethanol impairs, and SR rescues Y-maze enhanced pCaMKIV, pCaMKII, pCREB.•Ethanol impairs, and SR prevents Y-maze enhanced H3K14/H4K8ac and Arc expression.•Y-maze enhances H3K9me2 in postnatal ethanol exposed adult mice and was rescued by SR.•Arc expression is regulated by epigenetic modification on Arc gene promoter and rescued by Bix. Postnatal ethanol exposure has been shown to cause persistent defects in hippocampal synaptic plasticity and disrupt learning and memory processes. However, the mechanisms responsible for these abnormalities are less well studied. We evaluated the influence of postnatal ethanol exposure on several signaling and epigenetic changes and on expression of the activity-regulated cytoskeletal (Arc) protein in the hippocampus of adult offspring under baseline conditions and after a Y-maze spatial memory (SP) behavior (activity). Postnatal ethanol treatment impaired pCaMKIV and pCREB in naïve mice without affecting H4K8ac, H3K14ac and H3K9me2 levels. The Y-maze increased pCaMKIV, pCREB, H4K8ac and H3K14ac levels in saline-treated mice but not in ethanol-treated mice; while H3K9me2 levels were enhanced in ethanol-exposed animals compared to saline groups. Like previous observations, ethanol not only reduced Arc expression in naïve mice but also behaviorally induced Arc expression. ChIP results suggested that reduced H3K14ac and H4K8ac in the Arc gene promoter is because of impaired CBP, and increased H3K9me2 is due to the enhanced recruitment of G9a. The CB1R antagonist and a G9a/GLP inhibitor, which were shown to rescue postnatal ethanol-triggered synaptic plasticity and learning and memory deficits, were able to prevent the negative effects of ethanol on activity-dependent signaling, epigenetics and Arc expression. Together, these findings provide a molecular mechanism involving signaling and epigenetic cascad