Adolescent Alcohol Exposure: Burden of Epigenetic Reprogramming, Synaptic Remodeling, and Adult Psychopathology

Abstract

Adolescence represents a crucial phase of synaptic maturation characterized by molecular changes in the developing brain that shape normal behavioral patterns. Epigenetic mechanisms play an important role in these neuromaturation processes. Perturbations of normal epigenetic programming during adolescence by ethanol can disrupt these molecular events, leading to synaptic remodeling and abnormal adult behaviors. Repeated exposure to binge levels of alcohol increases the risk for alcohol use disorder (AUD) and comorbid psychopathology including anxiety in adulthood. Recent studies in the field clearly suggest that adolescent alcohol exposure causes widespread and persistent changes in epigenetic, neurotrophic, and neuroimmune pathways in the brain. These changes are manifested by altered synaptic remodeling and neurogenesis in key brain regions leading to adult psychopathology such as anxiety and alcoholism. This review details the molecular mechanisms underlying adolescent alcohol exposure-induced changes in synaptic plasticity and the development of alcohol addiction-related phenotypes in adulthood.

Epigenetic basis of the dark side of alcohol addiction

“…It has long been appreciated that exposure to alcohol in utero leads to fetal alcohol spectrum disorders (FASD), but more recent research has concluded that exposure to alcohol during adolescence also causes long-lasting alterations to brain and behavior (Coriate et al, 2013; Kyzar et al, 2016a). Both FASD and adolescent alcohol exposure cause changes in the expression of epigenetic enzymes and chromatin conformation.…”

“…Adolescence is a critical period for brain development (Keshavan et al, 2014; Kyzar et al, 2016a; Crews et al, 2016). While most organs do not undergo noteworthy changes during the lifespan with regards to structure and function, the brain goes through important changes during early life and adolescence.…”

“…In particular, individuals first exposed to alcohol during ages 11–14 have a 10–15 fold increased risk of developing alcohol dependence in adulthood compared to individuals who had their first experience with alcohol at age 19 or later (DeWit et al, 2000; Grant et al, 2001). This increased environmental risk has led researchers to use animal models to investigate the neuroadaptations occurring in the brain of adolescents exposed to alcohol that may persist until adulthood and exert lasting effects on behavior (Kyzar et al, 2016a). Importantly, numerous independent studies show that exposure to alcohol during adolescence increases the preference for alcohol in adulthood compared to non-ethanol exposed animals, thus recapitulating the clinical phenotype observed in epidemiological studies (Alaux-Cantin et al, 2013; Broadwater and Spear, 2013; Gilpin et al, 2012; Pandey et al, 2015; Sakharkar et al, 2016).…”

Epigenetic mechanisms of alcoholism and stress-related disorders

“…During adolescence, epigenetic modifications play an important role in neurodevelopment, and interfering with these mechanisms is a risk factor that can result in developing neuropsychiatric disorders in adult life (Kyzar et al, 2016a). As observed in adult rats, acute alcohol treatment induced anxiolytic effects and the inhibition of HDAC activity in the amygdala of adolescent rats but required higher dose of ethanol as compared with adult rats (Sakharkar et al, 2012, 2014b).…”

“…An acute ethanol challenge in adulthood can attenuate the anxiety-like behavior, the decrease in Lsd1+8a (a neuron-specific splice variant of LSD1), and reverse the increase of dimethylated H3K9 levels of the BDNF exon IV gene promoter in the amygdala induced by AIE (Kyzar et al, 2016b). Together with adolescent studies on histone acetylation, all these data suggest that alcohol exposure during early life or in adulthood can cause epigenetic alterations leading to changes in gene expression that, in turn, can regulate alcohol-related behaviors (Kyzar et al, 2016a). …”