Glutamate and GABA receptor dysfunction in the fetal alcohol syndrome

The brain damaging effects of ethanol, as the most disabling component of the fetal alcohol syndrome (FAS), have been recognized for three decades, but the mechanism underlying these effects has remained elusive. Recently, we discovered that ethanol triggers widespread apoptotic neurodegeneration throughout the developing brain when administered to infant rodents during the period of synaptogenesis, also known as the brain growth spurt period. These findings provide a more likely explanation than has heretofore been available for the reduced brain mass and lifelong neurobehavioral disturbances associated with the human FAS. We propose that a dual mechanism—blockade of NMDA glutamate receptors and hyperactivation of GABA_A receptors—mediates ethanol's apoptogenic action, based on established evidence that ethanol has both NMDA antagonist and GABAmimetic properties, and our recent finding that other drugs with either NMDA antagonist or GABAmimetic properties robustly trigger apoptotic neurodegeneration in the developing brain. The brain growth spurt occurs in different species at different times relative to birth. In rats and mice it is a postnatal event, but in humans it extends from the sixth month of gestation to several years after birth. Thus, there is a period in pre and postnatal human development, lasting for several years, during which immature CNS neurons are prone to commit suicide if exposed to intoxicating concentrations of drugs with NMDA antagonist or GABAmimetic properties. These findings are important, not only because of their relevance to the FAS, but because there are many agents in the human environment, other than ethanol, that have NMDA antagonist or GABAmimetic properties. Such agents include drugs that may be abused by pregnant mothers [ethanol, phencyclidine (angel dust), ketamine (Special K), nitrous oxide (laughing gas), barbiturates, benzodiazepines], and many medicinals used in obstetric and pediatric neurology (anticonvulsants), and anesthesiology (all general anesthetics are either NMDA antagonists or GABAmimetics).