Epilepsy — Animal Models & Behavioral Testing

The pilocarpine and intrahippocampal kainic acid models are the most widely used for chronic temporal lobe epilepsy. Both produce spontaneous recurrent seizures and hippocampal sclerosis, but the intrahippocampal KA model offers more focal, reproducible pathology with lower mortality.

After pilocarpine-induced SE, there is typically a seizure-free latent period of 1-4 weeks before spontaneous recurrent seizures begin. With intrahippocampal kainic acid, hippocampal paroxysmal discharges can appear within days, though convulsive seizures may take 2-3 weeks to emerge.

The 6-Hz corneal stimulation model at 44 mA intensity is specifically designed to identify compounds effective against pharmacoresistant seizures. It is resistant to phenytoin, carbamazepine, and lamotrigine, and is used by the NINDS Epilepsy Therapy Screening Program as a key differentiation assay.

A comprehensive battery typically includes the Morris Water Maze or Barnes Maze for spatial memory, fear conditioning for associative memory, novel object recognition for recognition memory, and the elevated plus maze for anxiety. Rotarod testing should be included to control for motor confounds, especially in drug studies.

Key strategies include using a ramping protocol (repeated low doses at 20-min intervals until SE onset), pretreatment with scopolamine methyl-bromide to block peripheral effects, and terminating SE with diazepam (5-10 mg/kg) after 60-90 minutes. Post-SE supportive care with saline injections and soft food also improves survival.

PTZ kindling uses repeated subconvulsive doses of the GABA-A antagonist pentylenetetrazol to progressively lower seizure threshold, scored on the Racine scale. Unlike electrical kindling (which requires stereotaxic electrode implantation), PTZ kindling is non-surgical, less technically demanding, and produces more generalized seizure onset patterns.

C57BL/6J mice work well for pilocarpine, kainic acid, and PTZ kindling models. However, they have relatively high seizure thresholds compared to strains like CF-1 or SWR/J. For the 6-Hz model, CF-1 mice are the traditional strain, though C57BL/6J can be used with adjusted stimulus parameters.

Allow at least 4-6 weeks after SE for stable chronic epilepsy to develop before beginning behavioral testing. This ensures you are measuring the effects of chronic epilepsy rather than acute post-SE recovery. Video-EEG monitoring during the waiting period confirms the presence of spontaneous seizures before behavioral assessment begins.