Abstract
Seizures induced by fever (febrile seizures) are the most frequent seizures affecting infants and children; however, their impact on the developing hippocampal formation is not completely understood. Such understanding is highly important because of the potential relationship of prolonged febrile seizures to temporal lobe epilepsy. Using an immature rat model, we have previously demonstrated that prolonged experimental febrile seizures render the hippocampus hyperexcitable throughout life. Here we examined whether (1) neuronal loss, (2) altered neurogenesis, or (3) mossy fiber sprouting, all implicated in epileptogenesis in both animal models and humans, were involved in the generation of a pro-epileptic, hyperexcitable hippocampus by these seizures. The results demonstrated that prolonged experimental febrile seizures did not result in appreciable loss of any vulnerable hippocampal cell population, though causing strikingly enhanced sensitivity to hippocampal excitants later in life. In addition, experimental febrile seizures on postnatal day 10 did not enhance proliferation of granule cells, whereas seizures generated by kainic acid during the same developmental age increased neurogenesis in the immature hippocampus. However, prolonged febrile seizures resulted in long-term axonal reorganization in the immature hippocampal formation: Mossy fiber densities in granule cell- and molecular layers were significantly increased by 3 months (but not 10 days) after the seizures. Thus, the data indicate that prolonged febrile seizures influence connectivity of the immature hippocampus long-term, and this process requires neither significant neuronal loss nor altered neurogenesis. In addition, the temporal course of the augmented mossy fiber invasion of the granule cell and molecular layers suggests that it is a consequence, rather than the cause, of the hyperexcitable hippocampal network resulting from these seizures.
Highlights
Febrile seizures have generated intense research efforts because of their high incidence (2–5% of children between the ages of 6 months and 5 years) and their potential relationship to limbic epilepsy (TLE) later in life
We have previously demonstrated that prolonged experimental febrile seizures cause transient neuronal injury, but do not result in acute hippocampal cell death (Toth et al, 1998)
kainic acid (KA)-induced seizures significantly increased the number of BrdU-labeled cells 3 days later (Figs. 4B, 5A vs 5C). This enhanced proliferation rate was transient: by 7 days after the seizures, granule cells (GCs) neurogenesis had returned to control levels (Fig. 4B). These results indicate that prolonged, intense developmental seizures are capable of influencing the proliferation rate of GC progenitors in the developing dentate gyrus (DG)
Summary
Febrile seizures (seizures induced by fever) have generated intense research efforts because of their high incidence (2–5% of children between the ages of 6 months and 5 years) and their potential relationship to limbic (temporal lobe) epilepsy (TLE) later in life (for review, see Lewis, 1999; Cendes and Andermann, 2002). Hyperthermic seizures of only 20 min duration caused acute hippocampal neuronal injury (Toth et al, 1998) and enhanced susceptibility to further limbic seizures throughout life (Dubé et al, 2000). This higher susceptibility to seizures was at least partially due to hyperexcitability of the hippocampal formation itself, that emerged within a week of the seizures The mechanisms that cause and sustain this enhanced hippocampal excitability have remained elusive
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