Mossy fiber plasticity and enhanced hippocampal excitability, without hippocampal cell loss or altered neurogenesis, in an animal model of prolonged febrile seizures

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.

Neuropeptide Y: Potential role in recurrent developmental seizures

“…The threshold temperatures generating experimental FS are close to those required for FS in normal children [14]. As indicated by seizure behavior and confirmed with electrophysiological recordings from multiple brain sites, these seizures are limbic and the behavior during the seizures is reproducible and stereotyped [10,18,32]. Seizure duration can be tightly controlled in the model.…”

“…In order to study the consequences of complex FS, and thus to gain a better understanding of their potential contribution to human epilepsy, an animal model of FS was established in our laboratory [10,18,19,32,33,73]. In this model, experimental FS are induced in rat pups on postnatal days 10 or 11, an age that corresponds to the hippocampal developmental stage at which human infants are most susceptible to febrile seizures (see comparison of developmental milestones in humans and rodent hippocampus in [4]).…”

“…Rats were then returned to their mothers and further investigated weeks or months later. The major findings of these studies are that prolonged FS do not lead to cell death nor to other neuroanatomical abnormalities, although transient neuronal injury occurs [10,11,33,35,73]. Nevertheless, rats that had experienced prolonged FS early in life have a reduced seizure threshold later in life and ~35% develop spontaneous seizures, i.e.…”

Choosing the Correct Antiepileptic Drugs: From Animal Studies to the Clinic

“…The seizures induce transient neuronal injury but no cell death [71,74]. T2-weighted signal changes have been found in the hippocampus following the hyperthermic seizures [75].…”

Novel Animal Models of Pediatric Epilepsy

“…The most studied mechanism to induce hyperthermia is the use of heated airstream on P10 to P11 rats [18]. No evidence of hippocampal neuronal loss (using Nissl stain counting methods) have been found [24], but hyperexcitability in brain slices and an increase in seizure susceptibility have been reported [25]. More recently, spontaneous recurrent seizures have been recorded using concurrent hippocampal and cortical EEG video EEG monitoring [26,27].…”