Gender-Dependent Actions of the Histone Deacetylase Blocker Sodium Valproate on Olfactory Learning in 129Sv Mice during the Early Postnatal Period

Abstract

The mechanisms supporting the long-term stable effects of early experience consist of modifications to chromatin, including histone acetylation, leading to changes in the structural relationships between DNA and histones [8,13,15,21]. Increases in levels of histone acetylation in brain and in the transcriptional activity of genes after treatment of animals with histone deacetylase blockers lead to improvements in learning [11,18,22]. This same effect is produced by high levels of maternal care in the first week of life [4], due to the resultant increase in the level of histone H3 acetylation close to the promoter of the glucocorticoid receptor gene (exon 1 7 of the GR promoter) in the hippocampus of adult offspring rats [20]. Our data indicate that the effectiveness of early learning is also determined by the level of maternal behavior. Thus, in 129Sv mice, in contrast to C57BL/6J mice, a low level of effectiveness of early olfactory training with simulation of maternal grooming is combined with low levels of maternal behavior in a test based on transfer of offspring to the nest [1]. Females of strain 129Sv have also been shown to devote less time grooming offspring than female C57BL/6J and NIH Swiss mice [7]. It can be suggested that there is a link between the effectiveness of early training and the level of histone acetylation in the brain. In adult animals, trichostatin A, sodium valproate, and sodium butyrate have been used as blockers of histone deacetylases [5]. The literature lacks reports validating the use of trichostatin A and sodium butyrate in young animals. In addition, trichostatin is dissolved in dimethylsulfoxide (DMSO), which is toxic to developing nervous systems [3]. Sodium valproate does not have these disadvantages. S.c. administration of sodium valproate at a dose of 50 mg/kg on postnatal day 1 is known to be well tolerated by mice and to produce significant increases in histone H3 acetylation in the brain [14]. For these reasons, we have selected sodium valThe processes of histone acetylation in the brain underlie both the mechanisms supporting the long-term stable effects of early experience, transmitted to offspring generations by epigenetic inheritance, and learning. However, the role of acetylation in learning has previously been studied only in adult animals: high levels of learning can be linked with high levels of histone H3 acetylation in the brain. The role of acetylation processes in the mechanisms of early learning has not been addressed. We report here our studies of the effects of blockade of histone deacetylation with sodium valproate, which increases the level of acetylation of histone H3, on the outcome of training to olfactory discrimination in 8-day-old mice of strain 129Sv, which have low levels of learning with simulation of maternal grooming. Four doses of sodium valproate, given from day 3 to day 6 of postnatal development, were found to have gender-dependent actions: there were selective improvements in learning in males but not females, though females showed this se...

Sex-Dependent Effects of the Histone Deacetylase Inhibitor, Sodium Valproate, on Reversal Learning After Developmental Arsenic Exposure

“…Preferential response to valproate has been previously reported: valproate administration has a significant effect on male, but not female, performance in some behavioral paradigms ( Burenkova et al, 2013 ). Further, while valproate has been shown to have neuroprotective effects in models of neurodegeneration, these effects are more substantial in males than in females ( Long et al, 2016 ).…”

The role of epigenetic mechanisms in the long‐term effects of early‐life adversity and mother–infant relationship on physiology and behavior of offspring in laboratory rats and mice

“…However, with the administration of smaller doses (such as 50 mg/kg), these effects are not observed (Johannessen & Johannessen, 2003). In our experiments, we showed that the blockade of HDACs by sodium valproate administered subcutaneously at a dose of 50 mg/kg on PND3‐6 led to an improvement in olfactory discrimination learning task with imitation of maternal grooming as positive reinforcement impaired by MS procedure in a gender‐dependent manner, that is, in males, but not in females (Burenkova et al., 2014b). At the same time, the use of this scheme of administration of valproate did not lead to a violation of the physical, somatosensory development and social behavior of 129Sv mice in the nesting period (Burenkova et al., 2015).…”

Effects of early-life stress and HDAC inhibition on maternal behavior in mice.

“…Taking into account the negative impact of MS during the first postnatal week on subsequent behavior of adult female offspring, our next intention was to study the possibility of prevention of this influence. For this purpose we proposed the use of pharmacological agent modulating these mechanisms, VPA which restored the olfactory discrimination learning of 129Sv neonatal mice impaired by MS in our previous work (Burenkova, Aleksandrova, & Zarayskaya, 2013). In response to a question—whether early life administration of VPA could restore the negative effects caused by early stress—mixed results have been revealed.…”