Abstract
Adolescent alcohol drinking is known to contribute to the development and severity of alcohol use disorders (AUDs) later in adulthood. Recent studies have shown that long non-coding RNAs (lncRNAs) are critical for brain development and synaptic plasticity. One such lncRNA is natural occurring brain-derived neurotrophic factor antisense (BDNF-AS) that has been shown to regulate BDNF expression. The role of BDNF-AS lncRNA in the molecular mechanisms of AUD is unknown. Here, we evaluated the expression and functional role of BDNF-AS in postmortem amygdala of either early onset or late onset alcoholics (individuals who began drinking before or after 21 years of age, respectively) and age-matched control subjects. BDNF-AS expression is increased in early onset but not in late onset AUD amygdala and appears to be regulated epitranscriptomically via decreased N6-methyladenosine on BDNF-AS. Upregulation of BDNF-AS is associated with a significant decrease in BDNF expression and increased recruitment of EZH2, which deposits repressive H3K27 trimethylation (H3K27me3) at regulatory regions in the BDNF gene in the early onset AUD group. Drinking during adolescence also contributed to significant decreases in activity-regulated cytoskeleton-associated protein (ARC) expression which also appeared to be mediated by increased EZH2 deposition of repressive H3K27me3 at the ARC synaptic activity response element. These results suggest an important role for BDNF-AS in the regulation of synaptic plasticity via epigenetic reprogramming in the amygdala of AUD subjects who began drinking during adolescence.
Highlights
Alcohol use disorders (AUDs) are chronic, debilitating psychiatric illnesses that contribute to considerable socioeconomic and health burden worldwide[1]
We aimed to determine if there are epigenetic changes mediated by brain-derived neurotrophic factor antisense (BDNF-AS) that are operative in the regulation of brain-derived neurotrophic factor (BDNF) expression in adolescence, and whether these changes persist into adulthood in the amygdala of human postmortem brains diagnosed with AUDs that began drinking before the age of 21
Our results appear to suggest that BDNF-AS is upregulated most likely via decreased RNA methylation in the amygdala of adult AUD population who began drinking during adolescence, but not in AUD subjects who began drinking in adulthood
Summary
Alcohol use disorders (AUDs) are chronic, debilitating psychiatric illnesses that contribute to considerable socioeconomic and health burden worldwide[1]. Adolescence is a critical period in brain development and adolescent drinking decreases orbitofrontal cortex activity and increases amygdala activity[3] leading to less executive control, more emotional impulsivity, alterations in decision-making, and have a higher risk to engage in risky behaviors and develop mental health problems later in life[4,5]. The amygdala acts as a hub for the processing of sensory signaling from cortical regions, and is involved in regulation of emotional reactivity, decision-making, and negative affective state of alcohol addiction[6,7]. Recent studies have begun to examine the molecular basis of these changes in the amygdala in preclinical models of adolescent alcohol exposure and have identified numerous potential molecular components, such as brain-derived neurotrophic factor (BDNF), that are involved in the development of alcohol dependence in adulthood[10,11,12]
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