Protective effects of S100B in the developing serotonergic system

Fetal alcohol syndrome (FAS) is a devastating development disorder that is caused by the consumption of alcohol during pregnancy. Children diagnosed with FAS invariably present with nervous system defects, ranging from difficulties in fine movement and behavioral disorders, to defects in brain growth and severe mental retardation. In rodents, fetal ethanol exposure produces a large (45–65%) and long-lasting decrease in serotonin content in the raphe regions of the brain stem; this reduction is important because decreases in endogenous serotonin severely slow the development of serotonergic neurons. However, most of this damage can be prevented by co-treatment with serotonergic 5-HT_1A agonists, such as buspirone or ipsapirone, during the embryofetal period.; The major hypothesis of this work was that the protective effects of 5-HT_1A agonists were mediated through the increased glial release of S100B, a calcium-binding growth factor reported to modulate serotonergic neuronal development. Studies were performed using in vivo and in vitro models to characterize the effects of ethanol and 5-HT_1A agonists on S100B in the central nervous system. Ethanol severely reduced the numbers of S100B-immunopositive glial precursor cells in the central nervous system, while the co-administration of 5-HT_1A agonists was able to prevent this effect. In situ hybridization studies that examined S100B mRNA in the CNS found that glial cells in the embryonic neuroepithelium were responsive to 5-HT_1A agonists.; In vitro work characterized the effects of ethanol and 5-HT_1A compounds on glial and neurons in greater detail. Exposure to ethanol resulted in the glial production of toxic factor or factors that reduced both neuronal and glial cell number in culture. Co-treatment of ethanol-exposed cultures with buspirone, a 5-HT_1A agonist, promoted glial and neuronal survival through the increased release of S100B. Pharmacological studies using combinations of agonists and WAY 100635, a selective 5-HT_1A antagonist, suggest that the release of S100B might be mediated through a novel 5-HT subtype. Taken together, these results indicate that serotonergic agonists may be useful agents in the treatment of fetal alcohol syndrome.