Apoptotic neurodegeneration in the developing brain

Apoptosis is a mechanism of crucial importance for normal brain development. In the immature mammalian brain and during a period of rapid growth (brain growth spurt/synaptogenesis period), neuronal apoptosis can be triggered by trauma or interference in the action of neurotransmitters. Transient blockade of glutamate N-methyl-D-aspartate (NMDA) receptors, or activation of gamma-aminobutyric acid (GABAA) receptors, causes millions of developing neurons to commit suicide. Agents that can trigger apoptotic neurodegeneration in the developing mammalian brain include anesthetics (ketamine, nitrous oxide, halothane, isoflurane, propofol), anticonvulsants (benzodiazepines, barbiturates) and drugs of abuse (ethanol, phencyclidine, ketamine). Ethanol, the most widely abused drug in the world, is both an NMDA antagonist and a GABAA agonist and can therefore trigger massive apoptotic neurodegeneration in the developing brain. This mechanism can explain the reduced brain mass and lifelong neurobehavioral disturbances associated with intrauterine exposure of humans to ethanol (fetal alcohol syndrome). in addition, since many of these apoptogenic agents are used in pediatric and obstetrical medicine for purposes of sedation, anesthesia and treatment of seizure disorders, further research will be required to ascertain the risk posed by exposing the developing human brain to compounds that act by this mechanism during the brain growth spurt period, which in humans starts in the third trimester of pregnancy and extends to several years after birth.