Abstracts

Rationale: The kainic acid (KA) model of temporal lobe epilepsy (TLE) has been used in mice for decades. The model is considered a reliable tool for studying TLE because of its similarities to human epilepsy, both in histopathologic changes, and symptomatology. After hippocampal injections of KA, animals first undergo a period of status epilepticus, followed by a latent period before the onset of spontaneous, recurrent seizures. The KA model is frequently utilized to evaluate therapies for temporal lobe epilepsy. However, the optimal dose of KA, and use of diazepam to interrupt status epilepticus, to both maximize seizures and minimize mortality, has not been fully determined in the mixed C57Bl/6 & SV129 mouse model.

Methods: Mice received unilateral intrahippocampal injections of either 75 or 150 nL KA. Animals underwent stereotactic placement of four cortical screw electrodes for electroencephalography, and two bare wire electrodes for electromyography. Within each dosage group, mice were further divided to receive either 10 mg/kg intraperitoneal diazepam or vehicle. Diazepam was administered 4-hours post-operative. Each group consisted of 3-4 mice (n=13, 5 male).


Results: Several animals demonstrated overt signs of clinical status epilepticus. One animal (150 nL KA, no Diazepam) died in the early post-operative period. Mouse brains were harvested, sectioned (50 µm), and either stained with cresyl violet to evaluate histopathology, or stained with fluoro-jade C to quantify apoptosis. Seizures were compared in the latent (days 4-8) versus late (days 9-12) periods. Average seizure frequency rates were compared in each group. Animals were recorded until death or day 12 post-operative. During the late period, the 150 nL KA group experienced an average of 0.225 seizures per day, which is twice the seizure rate observed in the 75 nL KA group (0.128 per day). Furthermore, the 150-nL group that received diazepam exhibited the same seizure rate as the no diazepam group, but demonstrated reduced mortality.


Conclusions: In this study, we found that adjusting the KA dose from 75 to 150 nL increased the spontaneous seizure rate during the late period. No change in mortality was seen when giving concomitant diazepam. This improvement to the model will allow for higher throughput preclinical testing of anti-seizure and anti-epileptogenic therapies.

Funding: This work was funded by NIH NINDS K08NS126730 and institutional funds.