Sudden Unexpected Death in Epilepsy and Respiratory Defects in a Mouse Model of DEPDC5‐Related Epilepsy

Abstract

ObjectivesDEPDC5 is a common causative gene in familial focal epilepsy with or without malformations of cortical development. Its pathogenic variants also confer a significantly higher risk for sudden unexpected death in epilepsy (SUDEP), providing opportunities to investigate the pathophysiology intersecting neurodevelopment, epilepsy, and cardiorespiratory function. There is an urgent need to gain a mechanistic understanding of DEPDC5‐related epilepsy and SUDEP, identify biomarkers for patients at high risk, and develop preventive interventions.MethodsDepdc5 was specifically deleted in excitatory or inhibitory neurons in the mouse brain to determine neuronal subtypes that drive epileptogenesis and SUDEP. EEG, cardiac, and respiratory recordings were performed to determine cardiorespiratory phenotypes associated with SUDEP. Baseline respiratory function and the response to hypoxia challenge were also studied in these mice.ResultsDepdc5 deletion in excitatory neurons in cortical layer 5 and dentate gyrus caused frequent generalized tonic–clonic seizures and SUDEP in young adult mice, but Depdc5 deletion in cortical interneurons did not. EEG suppression immediately following ictal offset was observed in fatal and non‐fatal seizures, but low amplitude rhythmic theta frequency activity was lost only in fatal seizures. In addition, these animals developed baseline respiratory dysfunction prior to SUDEP, during which ictal apnea occurred long before terminal cardiac asystole.InterpretationDepdc5 deletion in excitatory neurons is sufficient to cause DEPDC5‐related epilepsy and SUDEP. Ictal apnea and respiratory dysregulation play critical roles in SUDEP. Our study also provides a novel mouse model to investigate the underlying mechanisms of DEPDC5‐related epilepsy and SUDEP.This article is protected by copyright. All rights reserved.

Divergent Causes and Convergent Mechanisms of SUDEP

“…Although some SUDEP models, including the one reported here, have been reported to have interictal abnormalities of respiratory control, 19,23,30 fatal apnea occurs even in models in which interictal breathing is normal 21,26 . A more relevant observation may be that seizures cause profound postictal blunting of the ventilatory response to hypercapnia in some Scn1a R1407X mice and humans 20,26 .…”

“…For many of the existing mouse SUDEP models, death can be prevented by mechanical ventilation, [19][20][21]23,24 indicating that respiratory depression is required for death to occur. Does that mean there is not a role for cardiovascular dysfunction?…”

“…In this issue of Annals of Neurology , Kao et al 19 introduce a new mouse SUDEP model in which Depdc5 (disheveled, Egl‐10, and pleckstrin domain containing protein 5) was selectively deleted in neurons that express Rbp4 (retinol binding protein 4), which is found in excitatory neurons of the dentate gyrus and Layer 5 of the neocortex. DEPDC5 is a member of the GATOR1 complex, which inhibits mammalian target of rapamycin (mTOR).…”