Abstract
Alcohol consumption by pregnant women may produce neurological abnormalities that affect cognitive processes in children and are together defined as fetal alcohol spectrum disorders (FASDs). However, the molecular underpinnings are still poorly defined. In our earlier studies, we found that ethanol exposure of postnatal day 7 (P7) mice significantly induced widespread neurodegeneration mediated via endocannabinoids (eCBs)/cannabinoid receptor type 1 (CB1R). In the current study, we examined changes in the β-catenin protein levels that are involved in the regulation of neuronal function including neuronal death and survival. We found that moderate- and high-dose postnatal ethanol exposure (PEE) significantly reduced active-β-catenin (ABC) (non-phosphorylated form) protein levels in the hippocampus (HP) and neocortex (NC). In addition, we found that moderate- and high-dose PEE significantly increased the phosphorylated-β-catenin (p-β-catenin)/ABC ratios in the HP and NC. Antagonism/null mutation of CB1R before PEE to inhibit CC3 production mitigated the loss of ABC protein levels. Collectively, these findings demonstrated that the CB1R/β-catenin signaling mechanism causes neurodegeneration in neonatal mouse brains following PEE.
Highlights
Alcohol exposure during pregnancy can cause abnormal fetal development and functional anomalies to multiple brain regions that result in a broad spectrum of neurobehavioral and cognitive deficits termed fetal alcohol spectrum disorders (FASD) [1,2]
Postnatal ethanol exposure (PEE) in postnatal day 7 mice (P7) causes extensive neurodegeneration in several brain regions including the hippocampus (HP) and neocortex (NC) [14], which are vital for learning and memory [15]
The enhanced AEA/CB1R signaling pathway may be directly linked to the neurobehavioral abnormalities found in FASD [For recent review see [33]]
Summary
Alcohol exposure during pregnancy can cause abnormal fetal development and functional anomalies to multiple brain regions that result in a broad spectrum of neurobehavioral and cognitive deficits termed fetal alcohol spectrum disorders (FASD) [1,2]. Several mechanisms have been implicated in PEE-induced neurodegeneration in neonatal mice, our recent studies using pharmacological, genetic, and epigenetic tools suggest a significant role for the endocannabinoid (eCB)/cannabinoid receptor type 1 (CB1R) signaling pathways [22]. PEE activates several components of the eCB system, leading to neurodegeneration in neonatal mice and persistent synaptic, learning, and memory abnormalities in adult mice [19,20,31,32]. The enhanced AEA/CB1R signaling pathway may be directly linked to the neurobehavioral abnormalities found in FASD [For recent review see [33]]. We examined whether PEE, which activates several components of the eCB system leading to neurodegeneration in neonatal mice, inhibits the β-catenin signaling pathway in P7 mice. The findings suggest that PEE destabilizes β-catenin through enhanced phosphorylation of β-catenin followed by degradation, and this change is rescued by inhibition of CB1R
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