The Long Hangover: Adolescent Intermittent Ethanol's Effects on Hippocampal Neuroimmune and Cell Death Markers, Reversal by Donepezil



Adolescence is a critical period for the developing brain, and binge drinking during this neuromaturation can result in enduring abnormal brain function and behavior. Repeated adolescent binge ethanol drinking is associated with increased risk of alcohol use disorders, psychopathology, and cognitive dysfunction in adulthood. In rodents, adolescent intermittent ethanol (AIE) exposure causes diminished adult hippocampal neurogenesis and dendritic spine density in the hippocampal dentate gyrus.  Donepezil (Aricept), an anti-cholinesterase with microglial inhibitory actions, has been shown to reverse the effect of AIE on dendritic spine density.  Therefore, we hypothesized donepezil would reverse the AIE-induced decrease of dentate neurogenesis as well as AIE-induced neuroimmune and epigenetic changes that may underlie it.

AIE reduced immunoreactivity for hippocampal dentate gyrus doublecortin (DCX) and increased immunoreactivity for activated caspase-3 and death receptor-3 in adulthood.  Each of these effects was reversed by donepezil treatment in adulthood.  AIE also increased immunoreactivity for the inflammatory signaling molecules HMGB1 and its receptor RAGE, as well as the activated phosphorylated transcription factor pNFkB p65, and the gene silencing marker H3K9me2.  All of these AIE effects were also reversed by donepezil, with the exception of HMGB1. These findings suggest AIE blunts neurogenesis through persistent increases of neuroimmune gene expression that subsequently increase progenitor cell death.

These findings have mechanistic implications as AIE increased immunoreactivity for the RAGE receptor that is known to trigger a cascade that activates pNFkB. AIE increased pNFkB p65+IR, the transcriptionally active form, and H3K9me2, associated with reduced BDNF transcription.   These findings are consistent with AIE causing a persistent shift in proinflammatory/trophic gene expression through RAGE neuroimmune-epigenetic signaling mechanisms.

Learning Objectives:

1. Explain adolescent intermittent ethanol (AIE).

2. Identify important hippocampal neuroimmune and cell death markers and how they are affected by AIE.

3. Define the effective therapy.

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