Abstract
Fetal alcohol spectrum disorders (FASD) constitute a wide range of disorders that arise from prenatal exposure to ethanol (EtOH). However, detailed reports regarding the adverse effects of prenatal EtOH exposure on neocortical morphology and its underlying pathogenic mechanisms are limited. In the present study, we aimed to characterize the anatomical abnormalities of neocortical development and their correlation with microglial properties and neuro-inflammation in a mouse model of FASD. We evaluated the development and maturation of the neocortex in ICR mice prenatally exposed to 25% (w/v) EtOH using histological and molecular analyses. Reduced proliferation and excessive cell death were observed in the dorsal telencephalon. Abnormal neuronal distribution, layer formation, and dopaminergic neuronal projections were observed in the neocortex. Disruption of microglial differentiation (M1/M2 microglial ratio) and abnormal expression of pro-inflammatory and neurotrophic factors were induced, and these abnormalities were ameliorated by co-treatment with an anti-inflammatory drug (pioglitazone). FASD model mice displayed histological abnormalities, microglial abnormalities, and neuro-inflammation in both the embryonic and newborn stages. Thus, anti-inflammatory therapeutics may provide a novel preventive approach for the treatment of FASD.
Highlights
Fetal alcohol spectrum disorders (FASD) comprise a group of related disorders and conditions induced by prenatal exposure to ethanol (EtOH) resulting from maternal consumption
The specific abnormalities and underlying pathogenic molecular mechanisms associated with functional microglial differentiation (M1 versus M2) and morphology in mice subjected to prenatal EtOH exposure remain to be elucidated
We evaluated whether dopaminergic neuronal projections to the prefrontal cortex of newborns were affected by prenatal EtOH exposure using tyrosine hydroxylase (TH) immunostaining to mark dopaminergic neurons
Summary
Fetal alcohol spectrum disorders (FASD) comprise a group of related disorders and conditions induced by prenatal exposure to ethanol (EtOH) resulting from maternal consumption. Analyses of the adverse effects of prenatal EtOH treatment on the developing neocortex are important for clarifying the pathogenic mechanisms of developmental disorders and intellectual impairment in FASD. EtOH exposure has been reported to induce neuro-inflammation as well as excessive activation and apoptosis of microglia in the developing rodent neocortex[11,12,13,14]. The specific abnormalities and underlying pathogenic molecular mechanisms associated with functional microglial differentiation (M1 versus M2) and morphology in mice subjected to prenatal EtOH exposure remain to be elucidated. In the present study, we aimed to elucidate the pathogenic cellular and molecular mechanisms underlying the adverse effects associated with prenatal EtOH exposure and suggest a potential role for anti-inflammatory treatment in the prevention of FASD
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