Evolution of hippocampal epileptic activity during the development of hippocampal sclerosis in a mouse model of temporal lobe epilepsy

The effects of carbamazepine in the intrahippocampal kainate model of temporal lobe epilepsy depend on seizure definition and mouse strain

“…The finding that both HPDs and HVSWs could be suppressed by CBZ in male NMRI mice was unexpected, because previous studies reported that both types of electrographic seizures are resistant to CBZ when administered at doses of 20–50 mg/kg in male and female mice of different strains, including NMRI 5, 6, 10, 35. A similar effect of genetic background on resistance to an ASD (PHT) acting by modulation of sodium channels has recently been reported for the 6‐Hz mouse model of difficult‐to‐treat partial seizures 8.…”

“…Whereas HVSWs were not associated with behavioral alterations, HPDs, which occurred at a frequency of up to 60/h, were often associated with behavioral arrest, head nodding, or stereotyped behavior, such as exploration or grooming. HVSWs could sometimes also be recorded with some delay (8–12 ms) in the contralateral hippocampus (but never in the cerebral cortex), whereas the HPDs were observed only in the ipsilateral hippocampus (within 0.5 mm from the kainate injection site) and not contralaterally or in cerebral cortex 5. Riban et al5 suggested that HVSWs may be considered interictal events that are dissociated from seizures but that may initiate HPDs, whereas HPDs are focal nonconvulsive seizures resembling hypersynchronous high‐voltage spikes observed in sclerotic hippocampus of patients with TLE, particularly when this structure is the focus of epileptic activity.…”

“…Dose selection was based on previous studies in the same model5, 10 and in the 6‐Hz mouse model of difficult‐to‐treat partial seizures 9. Respective doses of CBZ are higher than those in traditional seizure models such as the maximal electroshock seizure (MES) test (ED 50 of CBZ ~8 mg/kg9), because both spontaneous seizures in the intrahippocampal kainate mouse model and seizures in the 6‐Hz mouse model are more difficult to suppress than are seizures in the MES test 5, 9, 10. Doses of CBZ exceeding 40 mg/kg were not tested, because the dose inducing “minimal neurological deficit” (or neurotoxicity) in 50% of mice (TD 50 ) in the rotarod test is about 45 mg/kg i.p 9…”

“…Induction of status epilepticus (SE) by unilateral intrahippocampal injection of kainate is associated with almost no mortality, and most mice develop ipsilateral hippocampal damage and highly frequent nonconvulsive or electrographic and less‐frequent convulsive seizures after SE 2, 4, 5. Riban et al5 were the first to report that epileptic electroencephalogram (EEG) activity recorded from the ipsilateral hippocampus in this model is resistant to major ASDs such as carbamazepine (CBZ), phenytoin (PHT), and valproate (VPA), whereas diazepam (DZP) was capable of suppressing these focal electrographic events.…”

“…The aim of the present study was therefore to evaluate whether the mouse strain also affects the pharmacology of epileptic EEG activity in the intrahippocampal kainate model. We chose CBZ for this study because it was repeatedly reported to be ineffective against epileptic EEG activity in this model 5, 6, 10. In contrast to these previous studies, the effect of CBZ was separately evaluated for HVSWs and HPDs to examine whether these paroxysmal EEG events respond differently to treatment.…”