Epilepsy, affecting over 70 million individuals worldwide, poses a significant risk of sudden death, known as SUDEP. The DEPDC5 gene is a common factor in familial focal epilepsy, with or without cortical malformations, and its pathogenic variants increase the susceptibility to SUDEP. This study aims to gain a mechanistic understanding of DEPDC5-related epilepsy and SUDEP, identify biomarkers for high-risk patients, and develop preventive interventions.Methods involved the targeted deletion of Depdc5 in nucleus tractus solitarius (NTS) neurons in the mouse brainstem, followed by the administration of pentylenetetrazol (PTZ) to induce seizures and SUDEP. Electroencephalogram (EEG), electrocardiogram (EKG), and respiratory recordings were conducted to assess cardiorespiratory phenotypes associated with non-fatal seizures and SUDEP. Baseline respiratory function and responses to hypoxia challenge were also studied.Results revealed that Depdc5 deletion in NTS neurons caused frequent non-fatal seizures and SUDEP in young adult mice. Simultaneous alterations in EEG, EKG, and breathing occurred during non-fatal seizures, with changes in breathing preceding fatal seizures. Additionally, these mice exhibited baseline respiratory dysfunction before induced seizures and SUDEP.Interpretation suggests that Depdc5 deletion in NTS neurons is sufficient to induce DEPDC5-related epilepsy and SUDEP, with respiratory dysregulation playing a crucial role. The study introduces a PTZ-evoked epilepsy mouse model for investigating the underlying mechanisms of DEPDC5-related epilepsy and SUDEP.