Dataset Information

Early Ethanol Exposure Inhibits the Differentiation of Hippocampal Dentate Gyrus Granule Cells in a Mouse Model of Fetal Alcohol Spectrum Disorders.

ABSTRACT:

Background

Alcohol consumption during pregnancy may damage the developing central nervous system of the fetus and lead to brain structural and functional deficits in the children, known as fetal alcohol spectrum disorders. The underlying mechanisms have not been fully elucidated. Previously, using a third trimester-equivalent mouse model, ethanol (EtOH)-induced behavioral deficits (including spatial learning and memory dysfunction) in the mice were detected on postnatal day (PD) 35. The hippocampal formation is critically involved in spatial learning/memory and contains 2 major neuron populations: the pyramidal cells in the hippocampus proper and the dentate gyrus granule cells (DGGCs) in the dentate gyrus (DG). In rodents, while the pyramidal cells are almost exclusively generated prenatally, the DG granule neurons are majorly generated during the first 2 weeks postnatally, which coincides with the period of EtOH exposure in our mouse model. Therefore, in the current study the effects of EtOH exposure on the development of the DGGCs were examined.

Methods

C57BL/6 mice were treated with 4 g/kg of EtOH by intubation on PD 4 to 10 to mimic alcohol exposure to the fetus during the third trimester in humans, and the development of DGGCs was examined by immunohistochemistry and quantified on PD 35.

Results

EtOH exposure does not affect the number of total or newly generated DGGCs, but reduces the number of mature DGGCs on PD 35 in both male and female mice. The ratio of immature DGGCs over total DGGCs was increased, and the ratio of mature DGGCs over total DGGCs was decreased by EtOH exposure. In addition, no sex-dependent effects of EtOH treatment were detected.

Conclusion

Our data indicate that EtOH exposure in mice during PD 4 to 10 does not affect the generation/proliferation but inhibits the differentiation of the DGGCs on PD 35.

SUBMITTER: Xu W

PROVIDER: S-EPMC7229810 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundInflammation during brain development participates in the pathogenesis of early brain injury and cognitive dysfunctions. Prenatal ethanol exposure affects the developing brain and causes neural impairment, cognitive and behavioral effects, collectively known as fetal alcohol spectrum disorders (FASD). Our previous studies demonstrate that ethanol activates the innate immune response and TLR4 receptor and causes neuroinflammation, brain damage, and cognitive defects in the developmental brain stage of adolescents. We hypothesize that by activating the TLR4 response, maternal alcohol consumption during pregnancy triggers the release of cytokines and chemokines in both the maternal sera and brains of fetuses/offspring, which impairs brain ontogeny and causes cognitive dysfunction.MethodsWT and TLR4-KO female mice treated with or without 10% ethanol in the drinking water during gestation and lactation were used. Cytokine/chemokine levels were determined by ELISA in the amniotic fluid, maternal serum, and cerebral cortex, as well as in the offspring cerebral cortex. Microglial and neuronal markers (evaluated by western blotting), myelin proteins (immunohistochemical and western blotting) and synaptic parameters (western blotting and electron microscopy) were assessed in the cortices of the WT and TLR4-KO pups on PND 0, 20, and 66. Behavioral tests (elevated plus maze and passive avoidance) were performed in the WT and TLR4-KO mice on PND 66 exposed or not to ethanol.ResultsWe show that alcohol intake during gestation and lactation increases the levels of several cytokines/chemokines (IL-1?, IL-17, MIP-1?, and fractalkine) in the maternal sera, amniotic fluid, and brains of fetuses and offspring. The upregulation of cytokines/chemokines is associated with an increase in activated microglia markers (CD11b and MHC-II), and with a reduction in some synaptic (synaptotagmin, synapsin IIa) and myelin (MBP, PLP) proteins in the brains of offspring on days 0, 20, and 66 (long-term effects). These changes are associated with long-term behavioral impairments, in the 66-day-old alcohol-exposed pups. TLR4-deficient mice are protected against ethanol-induced cytokine/chemokine production in alcohol-treated dams and offspring, along with synaptic and myelin alterations, and the log-term behavioral dysfunction induced by ethanol in offspring.ConclusionsThese results suggest that the immune system activation, through the TLR4 response, might play an important role in the neurodevelopmental defects in FASD.