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

Objectives DEPDC5 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 i...

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Bibliographic Details
Published in:Annals of neurology 2023-11, Vol.94 (5), p.812-824
Main Authors: Kao, Hsin‐Yi, Yao, Yilong, Yang, Tao, Ziobro, Julie, Zylinski, Mary, Mir, Mohd Yaqub, Hu, Shuntong, Cao, Runnan, Borna, Nurun Nahar, Banerjee, Rajat, Parent, Jack M., Wang, Shuo, Leventhal, Daniel K., Li, Peng, Wang, Yu
Format: Article
Language:English
Subjects:
Animals
Apnea
Apnea - complications
Biomarkers
Convulsions & seizures
Death, Sudden - etiology
Death, Sudden - prevention & control
Deletion
Dentate gyrus
EEG
Electroencephalography
Epilepsies, Partial - complications
Epilepsy
GTPase-Activating Proteins - genetics
Heart
Hypoxia
Interneurons
Mice
Neurons
Phenotypes
Respiratory function
Seizures
Seizures - complications
Sudden Unexpected Death in Epilepsy
Theta rhythms
Young adults
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Summary:Objectives DEPDC5 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. Methods Depdc5 was specifically deleted in excitatory or inhibitory neurons in the mouse brain to determine neuronal subtypes that drive epileptogenesis and SUDEP. Electroencephalogram (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. Results Depdc5 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 mice developed baseline respiratory dysfunction prior to SUDEP, during which ictal apnea occurred long before terminal cardiac asystole. Interpretation Depdc5 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. ANN NEUROL 2023;94:812–824
ISSN:0364-5134
1531-8249
DOI:10.1002/ana.26773