Immediate Epileptogenesis after Kainate-Induced Status Epilepticus in C57BL/6J Mice: Evidence from Long Term Continuous Video-EEG Telemetry

Abstract

The C57BL/6J mouse as a model of seizure/epilepsy is challenging due to high mortality and huge variability in response to kainate. We have recently demonstrated that repeated administration of a low dose of kainate by intraperitoneal route can induce severe status epilepticus (SE) with 94% survival rate. In the present study, based on continuous video-EEG recording for 4-18 weeks from epidurally implanted electrodes on the cortex, we demonstrate that this method also induces immediate epileptogenesis (<1-5 days post-SE). This finding was based on identification of two types of spontaneous recurrent seizures; behavioral convulsive seizures (CS) and electrographic nonconvulsive seizures (NCS). The identification of the spontaneous CS, stage 3-5 types, was based on the behaviors (video) that were associated with the EEG characteristics (stage 3-5 epileptiform spikes), the power spectrum, and the activity counts. The electrographic NCS identification was based on the stage 1-2 epileptiform spike clusters on the EEG and their associated power spectrum. Severe SE induced immediate epileptogenesis in all the mice. The maximum numbers of spontaneous CS were observed during the first 4-6 weeks of the SE and they decreased thereafter. Mild SE also induced immediate epileptogenesis in some mice but the CS were less frequent. In both the severe and the mild SE groups, the spontaneous electrographic NCS persisted throughout the 18 weeks observation period, and therefore this could serve as a chronic model for complex seizures. However, unlike rat kainate models, the C57BL/6J mouse kainate model is a unique regressive CS model of epilepsy. Further studies are required to understand the mechanism of recovery from spontaneous CS in this model, which could reveal novel therapeutic targets for epilepsy.

Electroencephalography and behavior patterns during experimental status epilepticus

“…In a recent study, high frequency of spike-wave discharges in EEG in animals with kainate-induced seizures were associated with central apnea 29 . Recent studies using the kainic acid model have emphasized that the frequency of generalized tonic-clonic seizures during SE determines its severity and outcome 6;8;30 . In the future, carefully designed studies to monitor cardiac and respiratory functions during experimental SE are needed to clarify the relationship between convulsive seizures and death and to elucidate the underlying neurobiological mechanisms.…”

“…These models are important tools in understanding the mechanisms of epileptogenesis 6;8 . These models have limitations when used to study the pathophysiology of SE.…”

Glial source of nitric oxide in epileptogenesis: A target for disease modification in epilepsy

“…For example, the SE induced by repeated low dose of kainate (i.p) in C57BL/6J mouse model produce severe SE, and continuous video-EEG confirmed that they develop epilepsy in less than 5 days (Puttachary et al, 2015b). A similar rapid epileptogenesis has been reported in the mouse pilocarpine model (Mazzuferi et al, 2012).…”

“…Interestingly, the clinical trial guidelines recommend ~5 min to intervene in the case of continuous convulsive seizures (Dodson et al, 1993; Lowenstein et al, 1999; Shinnar et al, 2001; Seinfeld et al, 2016). In chemoconvulsant animal models, it has been known that a minimum of 10 min of convulsive SE is sufficient to cause brain injury and to induce temporal lobe epilepsy (Nairismagi et al, 2004; Puttachary et al, 2015b). …”

“…The spontaneous CS persists for about 4–6 weeks, but they become infrequent thereafter. However, the electrographic non-convulsive seizures (NCS) persist for a longer period, i.e., up to 4 months post-SE (Puttachary et al, 2015b). Intra-hippocampal kainate administration in the mouse model also produced similar results with respect to infrequent CS, but frequent electrographic NCS (Klee et al, 2017) and widespread granule cell dispersion has been reported (Suzuki et al, 2005; Murphy and Danzer, 2011; Murphy et al, 2012; Hester and Danzer, 2014).…”