NER Rat Strain: A New Type of Genetic Model in Epilepsy Research

Abstract

Summary:Purpose: We characterized and evaluated as an animal model of epilepsy NER, a new epileptic rat strain, which was developed by inbreeding rats with spontaneous tonic-clonic seizures in a stock of Crj:Wistar.Methods: Animals were monitored through the inbreeding course, and video-EEGs were recorded selectively. External seizure-provoking stimuli were applied to NER and to a control parental strain. FI, F2, and backcross progenies were produced between NER and a nonepileptic unrelated strain. Pathologic study included hematoxylin-and-eosin (HE), Kliiver-Barrera's, modified Bodian silver, and neo-Timm's staining.Results: After the F9 generation, 94%-98% of NER exhibited spontaneous tonic-clonic convulsions, beginning with neck and forelimb clonus, wild jumpinghnning, opisthotonic posturing, and evolving to tonic, then clonic convulsion, followed by postictal flaccidity. Most seizure onsets occurred between 2 4 months of age, and the incidence was 0.45 k 0.21 seizures in 12 h. Ictal cortical and hippocampal EEGs were characterized by high-voltage spikes followed by diffuse spike-andwave or polyspike-and-wave complexes. NER revealed seizure susceptibility to pentylenetetrazol, tossing, and transcorneal electroshock, but not to tactile, photic, or acoustic stimuli, or to transauricular electroshock. Mating experiments revealed that 0% (0146) of the animals in F1,25.5% (1315 1) in F2, and 63.6%(56/88) in backcross progenies exhibited spontaneous tonicclonic convulsions without sex difference. For all these epileptic traits, no pathologic changes were demonstrated in the CNS.Conclusions: NER frequently exhibited spontaneous convulsions, controlled by a major autosomal recessive gene for epilepsy, that are comparable to generalized tonic-clonic seizures in humans. This can serve as a new genetic model in epilepsy research.

Enhanced Susceptibility to Spontaneous Seizures of Noda Epileptic Rats by Loss of Synaptic Zn2+

“…The basal activity before seizures (1) and the stages of seizures were observed as follows: beginning of aberrant activity on electroencephalogram without behavioral changes (2); asymmetric wave with myoclonus (3); high-voltage wave with tonic-clonic convulsion (4); low-voltage wave with postictal flaccidness (5). The component of γ-wave (7–9 Hz) (2, 6.9%; 3, 19.4%; 4, 15.4%; 5, 10.0%) became rhythmic during seizures as reported previously [26].…”

“…It is well known that epileptic seizures are closely linked to external stimuli in human. External stimui have been usually used for the analysis on tonic-clonic activity in spontaneous epilepsy animals [26], [33]. The hippocampal electroencephalogram during CQ (30 mg/kg)-induced convulsion was similar to that during sound-induced convulsions in NER reported previously [26].…”

“…On the basis of the controversial evidence on the action of synaptic Zn 2+ in experimentally induced seizures, in the present study, we used NER, a genetic model in epilepsy research to understand synaptic Zn 2+ function in susceptibility to spontaneous seizures. Adult NER frequently exhibit spontaneous convulsions, controlled by a major autosomal recessive gene for epilepsy, that are comparable to generalized tonic-clonic seizures in humans [26].…”

Application of Bicuculline to the Gerbil Somatosensory Cortex Induces Repetitive Ear Movements Accompanied by Induction of c-Fos Immunoreactivity in the Thalamus.

“…Our seizure-sensitive strain of gerbils does not show RBME in the absence of seizure-inducing stimuli, and it is thus possible that, when they receive a seizure-inducing stimulus, some transient phenomenon that inhibits GABA A receptor or brings similar situation occurs and starts RBME by a still unknown mechanism. Clarification of the mechanism underlying both types of RBME mentioned above and the possible roles of the SI may provide information on some of the stimulus-induced repetitive movements that are occasionally observed in epileptic animal species, including human beings [14,17,27,28].…”

Role of astroglial Kir4.1 channels in the pathogenesis and treatment of epilepsy

“…Although information on the mechanisms of Kir4.1 channels underlying the control of seizure induction is very limited, NER, a hereditary animal model of GTCS [31][32][33][34][35] , showed a region-specific reduction in the Kir4.1 channel expression in the amygdala [30] (Table 1). While no mutational changes in the Kir4.1-coding gene (Kcnj10) were observed in NER, Western blot analysis of the samples obtained under interictal conditions revealed that the expressional level of Kir4.1 (but not Kir5.1 or Kir2.1) was selectively diminished in the occipito-temporal cortex and thalamus among 10 brain regions examined (e.g., frontal, parieto-temporal and occipito-temporal cortex, hippocampus, striatum, thalamus, hypothalamus, midbrain, pons-medulla oblongata and cerebellum).…”