Ethanol-induced neuroapoptosis in the developing rodent cerebellum and related brain stem structures

For three decades since the fetal alcohol syndrome (FAS) was first described, researchers have been keenly interested in understanding the mechanism(s) by which ethanol damages or disrupts development of the human fetal brain. It has been reported repeatedly that exposure of infant rats to ethanol causes a reduction in brain mass and loss of cerebellar Purkinje cells, but the mechanisms underlying these effects have remained elusive. In a recent series of studies, we have demonstrated that exposure of infant rats or mice to ethanol on a single occasion during the synaptogenesis period of development causes neurons in many regions of the developing central nervous system to commit suicide (die by apoptosis), but the cerebellum was not among the brain regions focused upon in these studies. Here we show in infant rats and mice that one-time exposure to ethanol triggers acute neurodegeneration of Purkinje cells and other neurons in the cerebellar cortex, deep cerebellar nuclei, and two related brainstem nuclei (nucleus pontis, inferior olivary complex). We also describe the time course of neurodegeneration and window of vulnerability for each of these neuronal cell types and demonstrate that the cell death process in each case is unequivocally apoptotic. We conclude that exposure of infant rats or mice to ethanol on a single occasion during synaptogenesis can kill Purkinje cells, and many other neuronal populations at all levels of the developing neuraxis, and in each case the mechanism of cell death is apoptosis.