Pre-administration of G9a/GLP inhibitor during synaptogenesis prevents postnatal ethanol-induced LTP deficits and neurobehavioral abnormalities in adult mice

Abstract

It has been widely accepted that deficits in neuronal plasticity underlie the cognitive abnormalities observed in fetal alcohol spectrum disorder (FASD). Exposure of rodents to acute ethanol on postnatal day 7 (P7), which is equivalent to the third trimester of fetal development in human, induces long-term potentiation (LTP) and memory deficits in adult animals. However, the molecular mechanisms underlying these deficits are not well understood. Recently, we found that histone H3 dimethylation (H3K9me2), which is mediated by G9a (lysine dimethyltransferase), is responsible for the neurodegeneration caused by ethanol exposure in P7 mice. In addition, pharmacological inhibition of G9a prior to ethanol treatment at P7 normalized H3K9me2 proteins to basal levels and prevented neurodegeneration in neonatal mice. Here, we tested the hypothesis that pre-administration of G9a/GLP inhibitor (Bix-01294, Bix) in conditions in which ethanol induces neurodegeneration would be neuroprotective against P7 ethanol-induced deficits in LTP, memory and social recognition behavior in adult mice. Ethanol treatment at P7 induces deficits in LTP, memory and social recognition in adult mice and these deficits were prevented by Bix pretreatment at P7. Together, these findings provide physiological and behavioral evidence that the long-term harmful consequences on brain function after ethanol exposure with a third trimester equivalent have an epigenetic origin.

Adolescent alcohol exposure alters lysine demethylase 1 (LSD1) expression and histone methylation in the amygdala during adulthood

“…However, our data is not sufficient to exclude the possibility that other epigenetic enzymes are involved in AIE-induced neuroadaptation in the amygdala. For example, an increase in H3K9me2 due to increased G9a after ethanol exposure has been noted previously in models of neonatal alcohol exposure, leading to hippocampal neurodegeneration and deficits in long-term potentiation (Subbanna and Basavarajappa, 2014; Subbanna et al, 2014, 2013). …”

A single day of 5-azacytidine exposure during development induces neurodegeneration in neonatal mice and neurobehavioral deficits in adult mice

“…To identify the events involved in the neurodegenerative effects of 5-AzaC, we used Bix, SR and CB1RKO mice in our study to rescue 5-AzaC-induced activation of caspase-3 in P7 mice. In our earlier studies [22, 24, 35], we showed that a 1 mg/kg (Bix or SR) pretreatment was more effective at preventing alcohol-induced caspase-3 activation in P7 mice. We evaluated whether Bix or SR was effective in preventing 5-AzaC-induced caspase-3 activation in P7 mice.…”

“…The social recognition memory procedure [44, 45] allows direct access between the experimental and the stimulus mice and is widely used to assess long-term memory in rodents [22, 23, 44, 46, 47]. Briefly, three-month-old male mice that had been treated with saline or 5-AzaC at P7 (n = 8 mice from four different litters/group) were subjected to a social recognition memory test that was performed as described previously [22].…”

“…We administered 5-AzaC to P7 mice and evaluated DNA methylation, caspase-3 activation and signaling events in neonatal mice. To understand the mechanism of 5-AzaC, we also used cannabinoid receptor type 1 (CB1R) knockouts, histone methyltransferase (G9a) inhibitor or CB1R antagonist; all were shown to prevent caspase-3 activation in alcohol-treated P7 mice [22, 24]. At adulthood, we investigated long-term potentiation (LTP) and object, spatial and social memory behaviors.…”

Epigenetic Modifications, Alcoholic Brain and Potential Drug Targets

“…For instance, chronic alcohol consumption in humans can result in global and gene-specific increases in H3K4 trimethylation in the brain cortex [10], and either increase or decrease of this modification in promoters of specific genes in the hippocampus [50] . Recent evidence also shows that acute ethanol exposure alters dimethylation levels on lysines 9 and 27 of histone 3, which partially mediate ethanol's teratogenic effects in the brain [51] .…”