Molecular biological approach to explore the cause of brain damage after prenatal ethanol exposure

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To identify genes and factors which are responsible for brain alterations after prenatal ethanol exposure, we examined expression of genes and determination of neurotransmitters or neurotrophic factors in ethanol-exposed rat brains. Immunohistochemical study using anti-5-HT antibody revealed that prenatal ethanol exposure resulted in a reduction in the number and defects of migration of serotonin-positive neurons in the dorsal and medial raphe nuclei of rat fetuses. In ethanol-exposed rat fetuses, amounts of both 5-HT and its metabolite (5-HIAA) were decreased as well. RT-PCR analysis revealed a reduction of sonic hedgehog (Shh) expression in the brains of ethanol-exposed rat fetuses. Because Shh is related to the fate of 5-HT neuron, we concluded that prenatal exposure to ethanol impairs the development of 5-HT neurons, and this might have resulted in the reduction of Shh expressions. Therefore, the reduction of 5-HT neurons seen in the raphe persisted into adulthood, and prenatal ethanol-exposed rats showed anxiety-like behavior. In ethanol-exposed rat cerebellum, BDNF mRNA was decreased but NGF and its receptor (Trk A) mRNA expression were increased. Also, reduction of OMgp and GDNF mRNA expression was observed in the hippocampus and the septum nucleus, respectively. Thus, it is established that ethanol can affect expression of certain neurotrophic factors and their receptors. We monitored the intracellular calcium concentration after glutamate stimulation in ethanol-treated astrocytes derived from the hippocampus of neonatal rat (Day 3), and revealed that the glutamate-reactive cell number was decreased compared to non-ethanol-treated astrocytes. Since the calcium concentration in astrocytes might be related to maturation of synapse, the result suggests that ethanol may affect development of the neural circuit via a calcium signaling cascade in astrocytes.