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 gamma-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 approximately 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. Ca(2+) 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 Ca(2+) influx in addition to effects on postsynaptic GABA and glutamate receptors.
Moulder
Krista L
KL
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Fu
Tao
T
Melbostad
Heidi
H
Cormier
Robert J
RJ
Isenberg
Keith E
KE
Zorumski
Charles F
CF
Mennerick
Steven
S
D000818:Animals; D000831:Animals, Newborn; D015220:Calcium Channels / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000431:Ethanol / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology
D015220:Calcium Channels; D018079:Receptors, GABA; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases