Reduced seizure threshold and hippocampal cell loss in rats exposed to alcohol during the brain growth spurt

Background: Epilepsy is a prominent sign of neurologic dysfunction in some children with fetal alcohol syndrome (FAS). However, it is unknown whether the epileptic disorders in these children are directly due to the neurotera togenic effects of alcohol or to some other factor accompanying maternal al coholism. The hippocampus is vulnerable to alcohol-induced pathologic chang es, and dysfunction of the hippocampus often manifests as epilepsy. We exam ined the effect of alcohol exposure during development on the seizure thres hold and examined the relationship between alteration of seizure threshold and alcohol-induced neuronal loss from the hippocampus. Methods: Rat pups received 0.85, 2.5, or 3.75 g/kg of alcohol via intragast ric intubation daily over postnatal days (PD) 4-9. An intubated control and a suckle control group were also included. To assess the effect of a singl e day of alcohol exposure, an additional group received 3.75 g/kg of alcoho l on PD 4 alone. Behavioral seizure thresholds were determined by intraveno us infusion of the proconvulsant, pentylenetetrazol (PTZ), on PD 31 or on P D 90. In addition, electrographic seizure thresholds were determined by rec ording extracellular field potentials from the dentate gyrus. The number of hippocampal CA1 pyramidal cells, CA3 pyramidal cells, and granule cells of the dentate gyrus were determined by stereology. Results: Daily exposure to alcohol resulted in a dose-dependent decrease in the seizure threshold and in the selective loss of CA1 pyramidal cells. Re duction in the seizure threshold was significantly correlated with loss of CA1 pyramidal cells. Recordings of extracellular field potentials confirmed the alcohol-induced reduction in seizure threshold, demonstrated that PTZ- induced seizures involve hippocampal-parahippocampal circuitry, and provide d evidence that the hippocampal formation is the generator of the PTZ-induc ed seizures in alcohol-exposed animals. Conclusions: These findings demonstrate that exposure of the developing bra in to alcohol can permanently reduce the threshold for both behavioral and electrographic seizures and can selectively kill hippocampal CA1 pyramidal cells. Both the pathologic findings and the physiologic recordings support the concept that the reduced seizure threshold in alcohol-exposed animals i s due to hippocampal pathology.