Early life stress triggers sustained changes in histone deacetylase expression and histone H4 modifications that alter responsiveness to adolescent antidepressant treatment

Abstract

Early life stress can elicit long-lasting changes in gene expression and behavior. Recent studies on rodents suggest that these lasting effects depend on the genetic background. Whether epigenetic factors also play a role remains to be investigated. Here we exposed the stress-susceptible mouse strain Balb/c and the more resilient strain C57Bl/6 to a powerful early life stress paradigm, infant maternal separation. In Balb/c mice, infant maternal separation led to decreased expression of mRNA encoding the histone deacetylases (HDACs) 1, 3, 7, 8, and 10 in the forebrain neocortex in adulthood, an effect accompanied by increased expression of acetylated histone H4 proteins, especially acetylated H4K12 protein. These changes in HDAC expression and histone modifications were not detected in C57Bl/6 mice exposed to early life stress. Moreover, a reversal of the H4K12 hyperacetylation detected in infant maternally separated Balb/c mice (achieved with chronic adolescent treatment with a low dose of theophylline that only activates HDACs) worsened the abnormal emotional phenotype resulting from this early life stress exposure. In contrast, fluoxetine, a drug with potent antidepressant efficacy in infant maternally separated Balb/c mice, potentiated all histone modifications triggered by early life stress. Moreover, in non-stressed Balb/c mice, co-administration of an HDAC inhibitor and fluoxetine, but not fluoxetine alone, elicited antidepressant effects and also triggered changes in histone H4 expression that were similar to those provoked by fluoxetine treatment of mice exposed to early life stress. These results suggest that Balb/c mice develop epigenetic modifications after early life stress exposure that, in terms of the emotive phenotype, are of adaptive nature, and that enhance the efficacy of antidepressant drugs.

Histone Deacetylase Inhibition Rescues Maternal Deprivation-Induced GABAergic Metaplasticity through Restoration of AKAP Signaling

“…Moreover, childhood adversities trigger dysfunction in epigenetic control of neuronal activity and synaptic plasticity, thus having a significant impact on the brain and behavior (Rodenas-Ruano et al, 2012). Histone modifications are induced by MD through HDAC activity (Levine et al, 2012;Tesone-Coelho et al, 2015;Valvassori et al, 2014), suggesting the potential therapeutic benefits of early-life epigenetic intervention. These observations led us to hypothesize that early-life adversity engages epigenetic mechanisms regulating synaptic activity and learning mechanisms in VTA DA neurons and that these synaptic maladaptations may be reversed by HDACis if targeted soon after the insult.…”

The world of protein acetylation

“…A reduced histone acetylation might help to silence these repeats and thereby act protective towards several brain disorders such as Huntington's disease and fragile X syndrome [289,290]. Furthermore, a reduced H3 and H4 acetylation and increased expression of several HDACs (HDAC1, 2, 3, 8 and 10) are associated with stress responses in animals [291]. Followed by increased DNA methylation of the promoter regions of the glucocorticoid receptor gene (GR; Nr3c1) and a reduced GR transcription, this leads to a heightened stress response in the animals [292].…”

Severe Life Stress and Oxidative Stress in the Brain: From Animal Models to Human Pathology

“…Rodents and primates are the best suited species for conducting studies on the link between SLS, oxidative stress, and the development of psychiatric illnesses (97,176).…”