Glutamate signaling and the fetal alcohol syndrome

It has been known for three decades that ethanol, the most widely abused dr ug in the world, has deleterious effects on the developing human brain, but progress has been slow in developing animal models that are optimal for st udying this problem, and the underlying mechanisms have remained elusive. R ecently, we have shown that during the synaptogenesis period, also known as the brain growth spurt period, ethanol has the potential to trigger widesp read neuronal suicide (apoptosis), deleting many millions of neurons from t he in vivo mammalian brain. It appears that ethanol triggers apoptotic neur odegeneration by a dual mechanism (blockade of NMDA glutamate receptors and excessive activation of GABA receptors), in that ethanol has both NMDA ant agonist and GABAmimetic properties; we have shown that other drugs which ha ve either of these properties trigger apoptotic neurodegeneration in the de veloping brain. The brain growth spurt period in humans spans the last trim ester of pregnancy and the first several years after birth. Thus, our findi ngs provide a likely explanation for the reduced brain mass and neurobehavi oral disturbances associated with the human fetal alcohol syndrome. Further more, since NMDA antagonist and GABAmimetic drugs are sometimes abused by p regnant women and also are used as anticonvulsants, sedatives, or anestheti cs in pediatric medicine, our findings suggest the possibility that exposur e of the developing brain to these various drugs either pre or postnatally could contribute to mental disability syndromes that have heretofore been a ttributed to unknown causes. In addition, the observation that ethanol and related drugs trigger massive neuronal apoptosis in the developing brain pr ovides an unprecedented opportunity to study both neuropathological aspects and molecular mechanisms of apoptotic neurodegeneration in the in vivo mam malian brain. (C) 2001 Wiley-Liss, Inc.