Epigenetic mechanisms of alcoholism and stress-related disorders

“…other studies reported increased hippocampal neurogenesis in mice after acute or chronic alcohol consumption associated with enhanced brain-derived neurotrophic factor (BDNF) expression in this region together with impaired learning and memory (Stragier et al, 2015). In this regard, our results may be interpreted in terms of an epigenetic response to alcohol exposure due to the neuroadaptative mechanisms caused by early alcohol exposure (Palmisano and Pandey, 2017).…”

“…We previously evidenced corrective effects of a similar repeated diazepam administration on working memory alterations after a short (1-week) but not a long (6-weeks) withdrawal period ( 13 ). The failure of repeated diazepam administration to counteract the persistent cognitive and neurobiological disorders in 4-W-withdrawn mice may stem either from persistent alterations of GABAA receptors ( 68 – 70 ), increased downregulation of the GABAA receptors over repeated diazepam administration ( 71 ) or other alcohol-induced functional and structural neuroadaptations that may progressively develop over time after withdrawal, such as alterations of epigenetic mechanisms ( 12 , 72 , 73 ). Indeed, chronic exposure to alcohol produces brain adaptive changes in several neurotransmitter systems, including GABA, glutamate, and norepinephrine pathways ( 74 ) in order to compensate for alcohol-induced destabilization and restore neurochemical equilibrium ( 75 ).…”

“…The epigenetics of early life stress in relation to DA dysfunction and later-life health outcomes is of great interest considering that DA cell responses to early life stress can be epigenetically modulated during selective and sensitive windows of development. Epigenetic changes significantly impact the expression of genes controlling VTA DA neuronal function and signaling, which subsequently alter motivation and reward-related behaviors (Klengel and Binder, 2015; Palmisano and Pandey, 2017). Previously, we found that MD triggered an AKAP-dependent metaplasticity at GABAergic synapses onto VTA DA neurons in response to spike-timing-dependent plasticity (STDP) protocols that rendered GABAergic synapses more susceptible to LTD (Authement et al, 2015).…”

“…These GABAergic synaptic modifications were reversed to normal STDP by short-term in vitro HDAC inhibition using a pan-HDAC inhibitor (sodium butyrate) or a selective class I HDAC inhibitor (CI-994) (Figure 7). Indeed, adverse experiences in early life, such as MD, are associated with long-lasting changes in the expression of critical synaptic plasticity-associated genes through chromatin remodeling (Levine et al, 2012; Palmisano and Pandey, 2017; Pena et al, 2017; Rodenas-Ruano et al, 2012; Roth et al, 2009; Tesone-Coelho et al, 2013; Zhang et al, 2010). Based on this and our finding of normalization of STDP by acute in vitro HDAC inhibition, we hypothesized that MD-induced modifications in histone acetylation and HDAC2 expression in the VTA mediated MD-induced alterations in GABAergic STDP and AKAP signaling (Authement et al, 2015).…”