Alcohol Induces Parallel Changes in Hippocampal Histone H3 Phosphorylation and c‐Fos Protein Expression in Male Rats

Abstract

Background Changes in gene expression associated with alcohol-induced neuroadaptations are controlled in part by post-translational histone modifications. Serine 10 phosphorylation of histone H3 (H3S10ph) has been implicated in drug-induced changes in gene expression; however, ethanol’s effects on H3S10ph have yet to be examined in brain. Therefore, hippocampal H3S10ph was examined after acute alcohol exposure and alcohol dependence. Methods Adult male Sprague-Dawley rats received an acute exposure of ethanol (0–5 g/kg) via gavage. Or, rats were made alcohol dependent by administering 25% w/v ethanol every 8 hours for 4 days following a modified Majchrowicz protocol. In both cases, rats were perfused transcardially and paraformaldehyde-fixed brains were collected and processed for immunohistochemistry for H3S10ph or the immediate early gene, c-fos. Results Acute ethanol exposure dose-dependently altered the number of H3S10ph-positive (+) cells in the hippocampus. Specifically, 1 g/kg ethanol increased the number of H3S10ph+ cells in all neuronal layers, while 2.5 and 5 g/kg ethanol reduced the number of H3S10ph+ cells, an effect that was confined to the granule cell layer (GCL). In ethanol dependent rats, the number of H3S10ph+ cells in the GCL was reduced by 66% during intoxication; however, H3S10ph+ cells were increased in all neuronal layers during peak withdrawal. Subsequent examination of c-fos, a gene known to be regulated by H3S10ph, revealed that ethanol and withdrawal-associated changes in c-fos closely paralleled changes in H3S10ph. Conclusions These results suggest that H3S10ph regulates ethanol-mediated changes in c-fos expression, effects that likely have important implications for ethanol-induced changes in hippocampal neuronal plasticity.

LPS-induced histone H3 phospho(Ser10)-acetylation(Lys14) regulates neuronal and microglial neuroinflammatory response

“…We observed also a significant increase in H3S10ph after LPS treatment as also demonstrated in other animal models of brain insult, such as kainate or pilocarpine induced-epilepsy (Mori et al, 2013;Taniura et al, 2006), depression (Bagot et al, 2014;Nestler, 2014) and ethanol exposure (McClain and Nixon, 2016;McClung and Nestler, 2008). After LPS challenge, increase in H3S10ph levels appeared less region-and time-dependent than H3S10phK14ac as it was increased by a similar extent in both hypothalamus and hippocampus at 2 and 6 h post-LPS injection.…”

In Utero Alcohol Exposure and the Alteration of Histone Marks in the Developing Fetus: An Epigenetic Phenomenon of Maternal Drinking

“…Similar reports describe the alteration of histone H3 phosphorylation at the serine 10 and serine 28 residues in the rat liver 73 , 74 . Acute EtOH exposure altered the intensity of histone H3 phosphorylation at the serine 10 in the rat hippocampus 75 . Further investigation is needed to uncover direct evidence for prenatal alcohol exposure and the subsequent phosphorylation of histone protein.…”

Quantitative analysis of nanoscale intranuclear structural alterations in hippocampal cells in chronic alcoholism via transmission electron microscopy imaging

“…Previous studies have shown that histone modifications alter chromatin structure [28][29][30]. In addition, alcohol-mediated modifications of histones in the hippocampus have also been observed and reported [31,32]. Therefore, it is likely that ethanol feeding may have modified histones by methylation, acetylation or phosphorylation, which in turn may alter patterns of gene expression.…”