Developmental and seizure-related regional differences in immediate early gene expression and GABAergic abnormalities in the brain of EL mice

Murashima, Yoshiya L.; Kassamo, K; Suzuki, Jirô

doi:10.1016/s0920-1211(96)00034-4

Cited by 25 publications

(24 citation statements)

References 13 publications

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“…Recently, Kandel's group carried out an elegant study in which mice that lacked either nNOS or eNOS had essentially normal LTP, whereas mutant mice deficient in both nNOS and eNOS had substantially decreased LTP (17). electroencephalogram studies (3,18) and biochemical analyses of neurotransmitters, mitochondria1 function, and gene expression (5,7). By analogy with the neural plasticity in normal brains, both nNOS and eNOS may participate in this abnormal plasticity in EL mice.…”

Section: Discussionmentioning

confidence: 99%

“…For determination of NO metabolites EL[s] mice (low seizure threshold group) and EL[ns] mice (high seizure threshold group) of 20 weeks and 30 weeks of age (before and after the establishment of epileptogenesis, respectively) were used as described (5). There were six animals in each group.…”

Section: Preparation Of Tissuesmentioning

confidence: 99%

“…Several lines of evidence indicate that seizure discharges are initiated in the parietal area and then generalized through the hippocampus (3). These findings have been substantiated by histochemical and biochemical analyses of glucose utilization (4) and inhibitory neurotransmissions by aminobutyric acid (5). The developmental formation of the focus complex, which consists mainly of the parietal cortex and the hippocampus, has been hypothesized to be key to epileptogenesis in EL mice.…”

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confidence: 91%

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Role of Nitric Oxide in the Epileptogenesis of EL Mice

2000

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Summary:Purpose: To understand the role of nitric oxide (NO) in the regulation of seizures, we measured the extracellular levels of the NO metabolites nitrite and nitrate as indices of NO generation in the parietal cortex, hippocampus, and temporal cortex of EL mice. Furthermore, alterations of neuronal, endothelial, and inducible nitric oxide synthetase (nNOS, eNOS, and iNOS, respectively) were observed to correlate them with epileptogenesis.Methods: EL mice of 20 weeks and 30 weeks of age (before and after the establishment of epileptogenesis, respectively) were used. Nitrite was quantified using the specific absorbancy of diazo dye. NOS isoenzymes (nNOS, iNOS, and eNOS) were also investigated in the hippocampus during development until mice were 30 weeks old. Samples (total protein, 8.33 to 8.43 Fg) were separated by sodium dodecyl sulfate-polyacrylamide geI electrophoresis and identified by immunoblotting.Results: EL mice that experienced repetitive seizures showed a remarkable increase in nitrite in the hippocampus at 30 weeks of age compared with EL mice that had no experience of seizures. nNOS and iNOS were major and minor components, respectively, and both increased in parallel with the development of epileptogenesis. eNOS was not detectable.Conclusions: Excess iNOS (and subsequent increase in harmful NO) and deficient eNOS (and subsequent decrease in NO identified as an endothelium-derived relaxing factor) may work together to form a focus complex. Key Words: Epileptic mutant-EL mouse-Nitric oxide (NO)-Nitric oxide synthetase (NOS)-Abnormal plasticity-Epileptogenesis.The EL mouse is an inbred mutant strain that has been used as an animal model of secondarily generalized seizures (1,2). Several lines of evidence indicate that seizure discharges are initiated in the parietal area and then generalized through the hippocampus (3). These findings have been substantiated by histochemical and biochemical analyses of glucose utilization (4) and inhibitory neurotransmissions by aminobutyric acid (5). The developmental formation of the focus complex, which consists mainly of the parietal cortex and the hippocampus, has been hypothesized to be key to epileptogenesis in EL mice.In our recent studies, allopurinol, a xanthine oxidase inhibitor, exerted an antiepileptic action on EL mice (6), and the drug ameliorated abnormalities in the activities of the free radical scavenger superoxide dismutase isoenzymes, which are present in the hippocampus (7). Furthermore, DNA fragmentation was found in the hippocampal CA1 region and the parietal cortex in EL mice, presumably as a consequence of the production of free radicals attributable to decreased Cu,Zn-superoxide dismutase (7). Nitric oxide (NO) has been identified as a source of free radical oxidants with special relevance to pathological conditions in the brain, and reactive nitrogen intermediates could damage DNA as an important target (8). In addition, NO, identified as an endothelium-derived relaxing factor (9), is a potent vasodilator that regulates cerebral blo...

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Section: Discussionmentioning

confidence: 99%

Section: Preparation Of Tissuesmentioning

confidence: 99%

mentioning

confidence: 91%

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Role of Nitric Oxide in the Epileptogenesis of EL Mice

2000

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“…It should be noted, however, that chronically reduced c-fos mRNA expression is not consistently observed across all animal models of epilepsy, suggesting that frequent seizures may not be sufficient. Murashima et al [1996] measured c-fos mRNA expression in the EL mouse, whose seizures are provoked by external stimuli. EL mice exhibit continuously elevated levels of c-fos mRNA expression in both neocortex and hippocampus despite a history of frequent seizures.…”

Section: Neuronal Activation Is Dependent On Age Genotype and Brain mentioning

confidence: 99%

Developmental Seizure Susceptibility of Kv1.1 Potassium Channel Knockout Mice

Rho

Szot

Tempel³

et al. 1999

Dev Neurosci

108

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Potassium channels play a critical role in limiting neuronal excitability. Mutations in certain voltage-gated potassium channels have been associated with hyperexcitable phenotypes in both humans and animals. However, only recently have mutations in potassium channel genes (i.e. KCNQ2 and KCNQ3) been discovered in a human epilepsy, benign familial neonatal convulsions. Recently, it has been reported that mice lacking the voltage-gated Shaker-like potassium channel Kv1.1 α-subunit develop recurrent spontaneous seizures early in postnatal development. The clinical relevance of the Kv1.1 knockout mouse has been underscored by a recent report of epilepsy occurring in a family affected by mutations in the KCNA1 locus (the human homologue of Kv1.1) which typically cause episodic ataxia and myokymia. Here we summarize preliminary studies characterizing the developmental changes in seizure susceptibility and neuronal activation in the three genotypes of Kv1.1 mice (–/–, +/–, +/+). Using behavioral and immediate-early gene indicators of regional brain excitability, we have found that a seizure-sensitive predisposition exists in Kv1.1 –/– animals at a very young age (P10), before either spontaneous seizure activity or changes in c-fos mRNA expression can be demonstrated. Kv1.1 +/– mice, although behaviorally indistinguishable from wild types, also have an increased susceptibility to seizures at a similar early age. The Kv1.1 knockout mouse possesses many features desirable in a developmental animal epilepsy model and represents a clinically relevant model of early-onset epilepsies.

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“…In this model, DNA fragmentation in the hippocampus CA1 and the parietal cortex [1,2] has been demonstrated using in situ terminal transferase-mediated dUTP Nick labeling [1,3]. However, in the hippocampus and the parietal cortex of EL mice, neuronal cell loss is not found despite occurrence of frequent seizures during development [4,5].…”

Section: Introductionmentioning

confidence: 99%

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

Murashima

Yoshii

2010

E&S

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We have reported that cyclins and the corresponding cyclin-dependent kinase (CDK) family are related to cell proliferation during development as well as epileptogenesis. In the present study, we used EL mice to examine how levetiracetam (Lev) controls the altered expressions of cyclins and the CDK family during development, and further, the epileptogenesis as well in the parietal cortex, the seizure initiation site of EL. Developmental changes in the expression of cyclin and the corresponding CDK families (cyclin D/CDK-4, cyclin E/CDK-2, cyclin A/CDK-2, cyclin A/ CDK-1, and cyclin B/CDK-1) in the parietal cortex of EL mice and the control DDY mice were examined by Western blotting. At different ages, one group of mice (n = 6) were administered a single dose of Lev 160 mg/kg Lev p.o. and a treatment naïve group (n = 6) was administered vehicle, three days before sacrifice. Compared with the control DDY mice, treatment naïve EL mice showed upregulations of cell cycle-specific cyclins/ CDK during the early developmental stages, suggesting that reentry into cell cycle is promoted prior to the beginning of seizures. Lev abolished these effects and Lev-treated EL mice showed no seizures at all. These results suggest that cyclins/CDK may be activated during early stages of development before exhibiting seizures, suggesting that reentry into cell cycle in the parietal cortex is a candidate mechanism for the seizure predisposition of EL mice. The antiepileptic effects of Lev may be related to regulation of cell cycle reentry.

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Developmental and seizure-related regional differences in immediate early gene expression and GABAergic abnormalities in the brain of EL mice

Cited by 25 publications

References 13 publications

Role of Nitric Oxide in the Epileptogenesis of EL Mice

Role of Nitric Oxide in the Epileptogenesis of EL Mice

Developmental Seizure Susceptibility of Kv1.1 Potassium Channel Knockout Mice

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

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