Abstract
Heavy alcohol exposure causes profound damage to the adolescent brain, particularly the hippocampus, which underlie some behavioral deficits. However, the underlying molecular mechanisms remain inconclusive. The current study sought to determine whether binge alcohol exposure affects the hippocampus-related behaviors and key signaling proteins that may mediate alcohol neurotoxicity in adolescent rats. Alcohol exposure reduced the number of both NeuN-positive and doublecortin-positive cells in the hippocampus. Alcohol also induced neurodegeneration which was confirmed by ultrastructural analysis by electronic microscopy and was accompanied with the activation of microglia. Binge alcohol exposure impaired spatial learning and memory which was evaluated by the Morris water maze. However, alcohol did not alter the spontaneous locomotor activity which was determined by the open field test. GSK3β is a multi-function serine/threonine protein kinase regulating both neuronal survival and neurogenesis and plays an important role in various neurodegenerative disorders. We have previously shown that GSK3β is a key mediator of alcohol-induced neuron apoptosis in the developing brain. We showed here binge alcohol exposure caused GSK3β activation by inducing dephosphorylation at Ser9 without affecting the phosphorylation of Tyr216 in the hippocampus. Thus, GSK3β may be involved in binge alcohol exposure-induced neuronal damage to the adolescent hippocampus.
Highlights
During adolescence, the brain is undergoing maturation
We showed that binge alcohol exposure causes neurodegeneration and microglial activation in the hippocampus
Alcohol activated Glycogen synthase kinase 3β (GSK3β) by inducing Ser[9] dephopshorylation in the hippocampus. We confirmed that this paradigm of binge alcohol exposure significantly reduced the number of both mature neurons and newly formed neurons (DCX-positive) (Fig. 1)
Summary
This process involves changes in neurotransmission and plasticity which is accompanied with structural modifications in some brain regions, such as the hippocampus, prefrontal cortex and the limbic system structures[11]. Both clinical and experimental studies have provided evidence showing that alcohol exposure profoundly affected adolescent brain, such as memory impairments[12], structural alterations[13] and inflammatory brain damage[14]. We sought to determine whether binge alcohol exposure activates GSK3β in the adolescent brain
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