Ictogenesis and Epileptogenesis in EL Mice

Abstract

Summary:Purpose: In EL mice, ictogenesis is established at age ∼10 weeks, whereas epileptogenesis is induced through an experience of repetitive seizures during development. An "abnormal neural plasticity" has been suggested to be involved in these pathologic processes. It also is known that two isoforms of nitric oxide (NO) synthetase (nNOS and eNOS) are essential for the long-term potentiation (LTP), a plastic response of neurons. It appears, therefore, that these NO synthetases might play a major role in the establishment of abnormal neural plasticity. The purpose of the present study was to investigate ictogenesis and epileptogenesis by observing alterations of NO synthetases as well as immediate early gene (IEG) expressions and ␥-aminobutyric acid (GABA) distributions in the brain during development and with respect to seizure history.Methods: IEG (c-fos and zif) expression in EL mice were analyzed by in situ hybridization with 35S. Distribution of GABA concentrations and glutamic acid decarboxylase (GAD) activities in the parietal cortex of EL mice was quantitatively determined using ultramicroenzymatic chemistry (Lowry, 1978). Three isoforms of NOS were assayed by immunoblotting analysis for hippocampal tissues of EL mice and their control animals, DDY mice. DNA fragmentation was detected with the TUNEL method.Results: In EL mouse brains, IEG expression was related to the seizure history, seizure threshold, and age. Even in the interictal period, the animals expressed IEG continuously when their seizure thresholds were very low. Among various IEG expression sites in the brain, hippocampal CA1 was the most remarkable. These IEG expression sites were almost identical to the brain regions of EL mice where GABA concentrations and GAD activities were altered. Unexpectedly, the eNOS content of EL was very small, although eNOS appears to be responsible for NO that mediates an increase in local cerebral blood flow during focal seizures. nNOS, iNOS, and to a lesser extent, eNOS were essential to establish both ictogenicity and epileptogenicity. DNA fragmentation was observed in the hippocampus of EL mice in the interictal period.Conclusions: Continuous IEG expression and abnormal GABAergic function are involved in the epileptogenesis of EL mice. Transiently expressed IEG, on the other hand, is associated with the ictogenesis. It is conceivable that an excess amount of iNOS (and subsequent increase in harmful antimicrobial NO) and a lesser amount of eNOS (and subsequent decrease in NO or endothelium-derived relaxing factor, EDRF) may work together to contribute to a focus complex and ictogenesis. Drugs that suppress iNOS and/or potentiate eNOS may be promising candidates for a new type of antiepileptic agent. Key Words: Ictogenesis-Epileptogenesis-EL mouseAbnormal plasticity-Focus complex ICTOGENESIS AND EPILEPTOGENESIS IN EL MICE BRAIN RELATED TO IMMEDIATE EARLY GENE EXPRESSIONRapid genomic responses to neural stimulation may play a critical role in long-term synaptic plasticity. Recent works have strengthened th...

Antiepileptic effects of levetiracetam related to the regulation of cell cycle reentry in the parietal cortex of EL mouse brain

“…With respect to cell death-related proteins and neurotrophic factors in the brain, antiapoptotic Bcl-2 and pro-apoptotic Bax levels are increased during the periods of epileptogenesis in EL mice [6]. The neurotrophic factors NT-3 and BDNF increase significantly as Bcl-2 and Bax are elevated during epileptogenesis [6].…”

“…In addition, various cell death-related proteins are overexpressed during early stages of development. Pro-apoptotic Bax is overexpressed from 8 to 19 weeks of age, which covers the period of epileptogenesis [4,5,6]. In parallel, anti-apoptotic Bcl-2 is also overexpressed from 8 to 19 weeks of age.…”

“…In parallel, anti-apoptotic Bcl-2 is also overexpressed from 8 to 19 weeks of age. Expression of anti-apoptotic Bcl-X L peaks at 5 and 24 weeks of age, corresponding to early period of ictogenesis and late period of epileptogenesis, respectively [4,5,6]. There is an altered equilibrium between pro-apoptotic Bax and anti-apoptotic Bcl-2, which are associated with increased DNA fragmentation without cell loss [6].…”

“…Neurotrophic factor-3 (NT-3) shows a peak expression from 8 to 12 weeks of age, which covers the early period of epileptogenesis. In addition, fibroblast growth factor-2 (FGF-2) shows a linear increase in expression with age and reaches a maximum level at 24 weeks, which covers the late period of epileptogenesis [4,5,6]. On the other hand, seizure activity also induces expressions of neurotrophic factor mRNA and protein [7,8] and causes cell loss [9].…”

Stimulus-Induced Behavior in F1 Hybrids of Seizure-Sensitive and Seizure-Resistant Gerbils

“…EL mice also show a process of epileptogenesis: they begin to respond to certain kinds of stimuli at a comparable age to that of MGS gerbils and there are corresponding changes that probably reflect abnormal neuronal plasticity (Suzuki and Nakamoto, 1982;Murashima et al , 2002). When a mild stimulus was used to elicit generalized seizures, however, the F1 hybrids from a DDY female x EL male pair were more susceptible at 90 to 150 d than those from an EL female x DDY male pair (Todorova et al , 1999).…”