Abstracts

RATIONALE: Febrile seizures frequently precede medically intractable temporal lobe epilepsy associated with hippocampal atrophy, which can be cured by resection of the medial temporal lobe. These clinical observations have suggested that seizures occurring during a critical period in early postnatal development may induce long-term alterations in hippocampal circuits predisposing to episodes of neuronal synchronization and recurring seizures during adulthood. There is substantial evidence that an episode of seizures induced by kainic acid during the early postnatal period alters development of hippocampal circuitry and induces long-term alterations in hippocampal functional properties and behaviors that vary dramatically as a function of the postnatal age. To determine if febrile seizures induce long-term alterations in hippocampal circuitry which might influence seizure susceptibility during adulthood, the effects of febrile seizures during postnatal days P4-10, P11-17, and P20-26 on development of kindling, paired pulse inhibition, and seizure-induced alterations in inhibition were systematically assessed in adult rats at age P90.
METHODS: Rat pups experienced 3 febrile seizures evoked by exposure to hyperthermia (~ 40-41 [degree]C) every other day during one of the following postnatal periods: 1) P4-10, 2) P11-17, and 3) P20-26. At P90, these rats were evaluated for seizure susceptibility by assessing the rate of kindling evoked by electrical stimulation of the perforant path (twice daily 1 sec trains of 62Hz pulses). To assess the long-term effects of febrile seizures on functional properties and the balance of excitation and inhibition in hippocampal circuitry, paired pulse inhibition (PPI) was measured in the dentate gyrus of hippocampal slices from rats with preceding febrile seizures during P4-10, P11-17, and P20-26. To assess the effect of febrile seizures on seizure-induced plasticity in adulthood, PPI was assessed after repeated seizures evoked by electrical kindling or 30 mg/kg IP of pentylenetetrazol (PTZ) in P90 rats that experienced febrile seizures during P20-26, and was compared to the effects of kindling and PTZ in normal adult rats with no history of febrile seizures.
RESULTS: After febrile seizures occurring during P20-26, electrical kindling developed more rapidly (9.8 [plusminus] 1.7ADs to first Class V seizure) compared to normal adult controls (16.2 [plusminus] 1.5 ADs) and rats that experienced febrile seizures during P4-10 (14.7 [plusminus] 2.1ADs) or P11-17 (21.0 [plusminus] 4.7ADs, ANOVA, p[lt]0.05). In normal adult rats, repeated seizures evoked by kindling induce an increase in PPI in the dentate gyrus. In rats that experienced febrile seizures during P20-26, PPI in adulthood was reduced in the dentate gyrus compared to normal controls, and failed to increase after repeated seizures evoked by kindling.
CONCLUSIONS: The results demonstrate that febrile seizures during a critical period in early postnatal development increase susceptibility to seizures evoked by electrical or PTZ kindling in adulthood, decrease inhibition in the dentate gyrus, and induce alterations in responses to seizures during adulthood that would promote increased susceptibility to additional seizures and intractability.
[Supported by: the Epilepsy Foundation of America.]