Abstract
Epilepsy, a prevalent neurological disorder, is characterized by recurrent, self-sustained seizures resulting from abnormal neuronal hyperexcitability. Epilepsy encompasses a wide spectrum of etiologies, pathophysiological mechanisms, and treatment responses, resulting in considerable phenotypic heterogeneity. Over the past few decades, animal models, ranging from simple organisms to complex species, have played a pivotal role in elucidating the cellular, molecular, and circuit mechanisms underlying seizure generation and propagation, while also facilitating the development of antiseizure medication and other therapeutic interventions. This review first outlines the mechanistic basis of epilepsy and systematically summarizes existing seizure and epilepsy models across diverse taxa, including zebrafish, rodents, and non-human primates (NHPs), with a focus on model-specific features, translational relevance, and therapeutic utility. Despite substantial progress, limitations persist in recapitulating the full complexity of human epilepsy. Recent advances in genetic engineering, neuromodulation technology, and brain organoids are refining model fidelity and enhancing alignment with precision medicine approaches. Cross-species integration offers a promising avenue for bridging preclinical findings with clinical application, advancing mechanistic insight, and the development of targeted therapies.