Ethanol-induced death of postnatal hippocampal neurons

Fetal alcohol exposure causes severe neuropsychiatric problems, but mechanisms of the ethanol-associated changes in central nervous system development are unclear. In vivo, ethanol's interaction with N-methyl-D-aspartate (NMDA) and γ-aminobutyric acid type A (GABA_A) receptors may cause increased apoptosis in the immature forebrain. We examined whether ethanol affects survival of neonatal hippocampal neurons in primary cultures. A 6-day ethanol exposure killed hippocampal neurons with an LD50 of ∼25 mM. Elevated extracellular potassium or insulin-related growth factor 1 inhibited cell loss. Although potentiation of GABA_A receptors or complete block of NMDA receptors also kills hippocampal neurons, pharmacological studies suggest that ethanol's interaction with GABA_A and NMDA receptors is not sufficient to explain ethanol's effects on neuronal survival. Ca²⁺ influx in response to depolarization was depressed >50% by chronic ethanol treatment. We suggest that chronic ethanol may promote neuronal loss through a mechanism affecting Ca²⁺ influx in addition to effects on postsynaptic GABA and glutamate receptors.