Spontaneous Seizure Outcomes in Mice Using an Improved Version of the Pilocarpine Model of Temporal Lobe Epilepsy

Temporal lobe epilepsy (TLE) is a debilitating disorder that affects millions of people worldwide and is difficult to treat with medicines. There has been little progress in the development of novel therapies for these patients because of the lack of suitable animal models. Current rodent models of TLE use chemoconvulsants or electrical stimulation to induce status epilepticus, which evolves into chronic epilepsy with spontaneous recurring seizures. These models have face validity in human TLE as they share similarities with seizure onset in the hippocampus, EEG patterns, tonic-clonic convulsions behavior, and hippocampal sclerosis. Unfortunately, seizure frequencies are so variable that they hinder drug testing. The ideal model for screening epilepsy therapies would have spontaneous seizure frequencies that are greater than two per day, little-to-no seizure-free days, and would maintain these features for more than 4 weeks. This study describes a series of improvements to the mouse pilocarpine TLE model. First, a pharmacokinetic model was developed to guide pilocarpine dosing. Second, induction was combined with EEG monitoring, allowing for real-time monitoring of pilocarpine-induced EEG discharges and electrographic seizures that precede behavioral manifestations. Third, strains of mice were identified that withstand pilocarpine-induced status epilepticus and reliably develop spontaneous recurring seizures. The pilocarpine model was improved by lowering mortality and increasing the fraction of mice that developed spontaneous seizures and had seizure frequencies that are amenable to drug screening. Future studies are required to identify the ideal mouse strain for drug screening and validate the response to known anti-epileptic drugs.