Development of spontaneous recurrent seizures accompanied with increased rates of interictal spikes and decreased hippocampal delta and theta activities following extended kindling in mice.

Interictal epileptiform discharges refer to aberrant brain electrographic signals between seizures and feature intermittent interictal spikes (ISs), sharp waves, and/or abnormal rhythms. Recognition of these epileptiform activities by electroencephalographic (EEG) examinations greatly aids epilepsy diagnosis and localization of the seizure onset zone. ISs are a major form of interictal epileptiform discharges recognized in animal models of epilepsy. Progressive changes in IS waveforms, IS rates, and/or associated fast ripple oscillations have been shown to precede the development of spontaneous recurrent seizures (SRS) in various animal models. IS expressions in the kindling model of epilepsy have been demonstrated but IS changes during the course of SRS development in extended kindled animals remain to be detailed. We hence addressed this issue using a mouse model of kindling-induced SRS. Adult C57 black mice received twice daily hippocampal stimulations until SRS occurrence, with 24-h EEG monitoring performed following 50, 80, and ≥ 100 stimulations and after observation of SRS. In the stimulated hippocampus, increases in spontaneous ISs rates, but not in IS waveforms nor IS-associated fast ripples, along with decreased frequencies of hippocampal delta and theta rhythms, were observed before SRS onset. Comparable increases in IS rates were further observed in the unstimulated hippocampus, piriform cortex, and entorhinal cortex, but not in the unstimulated parietal cortex and dorsomedial thalamus. These data provide original evidence suggesting that increases in hippocampal IS rates, together with reductions in hippocampal delta and theta rhythms are closely associated with development of SRS in a rodent kindling model.

Convulsive behaviors of spontaneous recurrent seizures in a mouse model of extended hippocampal kindling.

Growing studies indicate that vigilance states and circadian rhythms can influence seizure occurrence in patients with epilepsy and rodent models of epilepsy. Electrical kindling, referred to brief, repeated stimulations of a limbic structure, is a commonly used model of temporal lobe epilepsy. Kindling via the classic protocol lasting a few weeks does not generally induce spontaneous recurrent seizures (SRS), but extended kindling that applies over the course of a few months has shown to induce SRS in several animal species. Kindling-induced SRS in monkeys and cats were observed mainly during resting wakefulness or sleep, but the behavioral activities associated with SRS in rodent models of extended kindling remain unknown. We aimed to add information in this area using a mouse model of extended hippocampal kindling. Middle-aged C57 black mice experienced ≥80 hippocampal stimulations (delivered twice daily) and then underwent continuous 24 h electroencephalography (EEG)-video monitoring for SRS detection. SRS were recognized by EEG discharges and associated motor seizures. The five stages of the modified Racine scale for mice were used to score motor seizure severities. Seizure-preceding behaviors were assessed in a 3 min period prior to seizure onset and categorized as active and inactive. Three main observations emerged from the present analysis. (1) SRS were found to predominantly manifest as generalized (stage 3-5) motor seizures in association with tail erection or Straub tail. (2) SRS occurrences were not significantly altered by the light on/off cycle. (3) Generalized (stage 3-5) motor seizures were mainly preceded by inactive behaviors such as immobility, standing still, or apparent sleep without evident volitional movement. Considering deeper subcortical structures implicated in genesis of tail erection in other seizure models, we postulate that genesis of generalized motor seizures in extended kindled mice may involve deeper subcortical structures. Our present data together with previous findings from post-status epilepticus models support the notion that ambient cage behaviors are strong influencing factors of SRS occurrence in rodent models of temporal lobe epilepsy.