Advantages of Repeated Low Dose against Single High Dose of Kainate in C57BL/6J Mouse Model of Status Epilepticus: Behavioral and Electroencephalographic Studies

Abstract

A refined kainate (KA) C57BL/6J mouse model of status epilepticus (SE) using a repeated low dose (RLD) of KA (5 mg/kg, intraperitoneal; at 30 min intervals) was compared with the established single high dose (SHD) of KA (20 mg/kg, intraperitoneal) model. In the RLD group, increased duration of convulsive motor seizures (CMS, Racine scale stage ≥3) with a significant reduction in mortality from 21% to 6% and decreased variability in seizure severity between animals/batches were observed when compared to the SHD group. There was a significant increase in the percentage of animals that reached stage-5 seizures (65% versus 96%) in the RLD group. Integrated real-time video-EEG analysis of both groups, using NeuroScore software, revealed stage-specific spikes and power spectral density characteristics. When the seizures progressed from non-convulsive seizures (NCS, stage 1–2) to CMS (stage 3–5), the delta power decreased which was followed by an increase in gamma and beta power. A transient increase in alpha and sigma power marked the transition from NCS to CMS with characteristic ‘high frequency trigger’ spikes on the EEG, which had no behavioral expression. During SE the spike rate was higher in the RLD group than in the SHD group. Overall these results confirm that RLD of KA is a more robust and consistent mouse model of SE than the SHD of KA mouse model.

Repeated low-dose kainate administration in C57BL/6J mice produces temporal lobe epilepsy pathology but infrequent spontaneous seizures

“…Our findings confirm a previous report (Tse et al, 2014) that low-dose, repeated KA administration serves as a useful paradigm for high rates of SE induction with limited mortality in C57BL/6J mice. Unique to our study, we demonstrate cell death can be readily observed in the hippocampus and limbic structures following repeated, low-dose KA administration in C57 mice.…”

“…We observe that systemic, low-dose KA administration (i.p.) reliably produces SE without acute mortality (7d), similar to reports by Tse et al (2014). Additionally, low-dose KA insults result in features indicative of TLE pathology, including hippocampal neurodegeneration and astrogliosis.…”

“…Our second approach was to test another low-dose KA injection paradigm for C57BL6/J mice that was published previously. In this paradigm, described by Tse et al (2014), C57 mice are administered KA (5 mg/kg, i.p.) until the first Racine stage 5 seizure is observed.…”

“…In this “5 mg/kg” injection paradigm, animals (N=3; weight: 20-24g) received 5 mg/kg injections of KA every 20 minutes until an initial Racine stage 5 seizure was observed, modified from (Tse et al, 2014). Animals displaying an initial Racine stage 3 seizure received a 2.5 mg/kg injection if a Racine stage 4/5 seizure was not observed before the time of next injection.…”

“…To monitor electrographic SE, one hour of baseline EEG was recorded before cohorts were injected with KA according to the ex-KA/VPA, ex-KA/NaCl, or 5 mg/kg KA paradigm (Tse et al, 2014). Changes in electrographic power (1-100Hz, 90s window, 45s step) during KA injections were plotted across a 24h period that included 1h of baseline activity used to normalize EEG power spectra.…”