On-demand seizures facilitate rapid screening of therapeutics for epilepsy

Animal models of epilepsy are critical in drug development and therapeutic testing. However, dominant methods for evaluating epilepsy treatments face a tradeoff between higher throughput and etiological relevance. Screening models are either based on acutely induced seizures in wild-type, naive animals or spontaneous seizures in chronically epileptic animals. Each has its disadvantages - acute convulsant or kindling-induced seizures do not account for the myriad neuropathological changes in the diseased, epileptic brains, and spontaneous behavioral seizures are sparse in chronically epileptic models, making it time-intensive to sufficiently power experiments. In this study, we developed the Opto-IHK (optogenetically induced seizures in intrahippocampal kainate mice) model, a mechanistic approach to precipitate seizures 'on demand' in chronically epileptic mice. We briefly synchronized principal cells in the CA1 region of the diseased hippocampus to reliably induce stereotyped on-demand behavioral seizures. These induced seizures resembled naturally occurring spontaneous seizures in the epileptic animals and could be stopped by commonly prescribed anti-seizure medications such as levetiracetam and diazepam. Furthermore, we showed that seizures induced in chronically epileptic animals differed from those in naive animals, highlighting the importance of evaluating therapeutics in the diseased circuit. Taken together, we envision the Opto-IHK model to accelerate the evaluation of both pharmacological and closed-loop interventions for epilepsy.