Rodent models of chronic epilepsy and their translational relevance to human disease

Chronic epilepsy (CE), characterized by spontaneous recurrent seizures (SRS), affects nearly 50 million people worldwide and remains a major unmet clinical challenge. Rodent models are central to deciphering epileptogenic mechanisms and testing antiepileptic therapies, yet their translational validity varies widely. This mini review critically examines the principal strategies used to induce persistent seizures in rodents, namely chemical, electrical, structural, and genetic, and evaluates how well they replicate the clinical, pathological, and behavioral features of human epilepsy. Chemical models (e.g., pilocarpine, pentylenetetrazol) reliably generate seizures but differ in their ability to mimic temporal lobe versus generalized epilepsy. Electrical paradigms (e.g., amygdala kindling, electrically induced status epilepticus) offer precise control over seizure initiation but often fail to produce robust spontaneous recurrence. Structural models, including traumatic brain injury and febrile seizures, recapitulate specific etiologies yet show considerable inter-study variability. Genetic models provide unique insight into inherited epilepsies but typically capture only narrow phenotypic spectra. No single approach reproduces the full heterogeneity and complexity of human epilepsy. Progress will require refining existing models, integrating multimodal strategies, and aligning preclinical endpoints with clinically relevant outcomes to accelerate the discovery of effective, personalized antiepileptic therapies.