Rapid hippocampal kindling of mice as a model of sudden unexpected death in temporal lobe epilepsy.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of seizure-related death in people with epilepsy. Yet, its mechanisms remain poorly understood. While most epilepsy syndromes have no known genetic component, animal SUDEP models are often of rare monogenetic mutations. Here, we present a novel non-genetic mouse model of SUDEP, relevant to temporal lobe epilepsy, the most common seizure disorder. Our accelerated CA1 hippocampal kindling paradigm, referred to as 'rapid kindling', reliably produces a spectrum of seizure phenotypes with progressive severity, from no seizure behavior to severe non-fatal and fatal generalized tonic-clonic seizures. Simultaneous electroencephalographic, electrocardiographic, and plethysmographic recordings were performed in 21 male and female C57BL/6 J adult mice, to characterize seizure dynamics and cardiorespiratory function. Fatal seizures were preceded by seizure-induced apnea that began during the tonic phase and persisted postictally, followed by progressive bradycardia and terminal asystole, similar to what has been observed for SUDEP-like events in previous animal models. Fatal seizures occurred in 33% of 21 kindled mice, with the probability of apnea and mortality increased with repeated seizures. Non-fatal tonic seizures exhibited similar apnea that resolved postictally, while clonic seizures were never fatal despite occasionally producing shorter apneic episodes. Longer tonic phase duration leading to postictal cardiorespiratory collapse distinguished fatal from non-fatal tonic seizures. Our rapid kindling approach provides a clinically relevant, non-genetic platform that recapitulates key features of SUDEP in temporal lobe epilepsy and enables controlled investigation of the mechanisms linking seizures to fatal cardiorespiratory failure.