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

IF 8.1 1区医学 Q1 CLINICAL NEUROLOGY Annals of Neurology Pub Date : 2023-08-22 DOI:10.1002/ana.26773

Hsin-Yi Kao PhD, Yilong Yao PhD, Tao Yang PhD, Julie Ziobro MD, PhD, Mary Zylinski BS, Mohd Yaqub Mir PhD, Shuntong Hu MD, PhD, Runnan Cao PhD, Nurun Nahar Borna MD, PhD, Rajat Banerjee PhD, Jack M. Parent MD, Shuo Wang PhD, Daniel K. Leventhal, Peng Li PhD, Yu Wang MD, PhD

{"title":"Sudden Unexpected Death in Epilepsy and Respiratory Defects in a Mouse Model of DEPDC5-Related Epilepsy","authors":"Hsin-Yi Kao PhD, Yilong Yao PhD, Tao Yang PhD, Julie Ziobro MD, PhD, Mary Zylinski BS, Mohd Yaqub Mir PhD, Shuntong Hu MD, PhD, Runnan Cao PhD, Nurun Nahar Borna MD, PhD, Rajat Banerjee PhD, Jack M. Parent MD, Shuo Wang PhD, Daniel K. Leventhal, Peng Li PhD, Yu Wang MD, PhD","doi":"10.1002/ana.26773","DOIUrl":null,"url":null,"abstract":"<div>\n \n <section>\n \n <h3> Objectives</h3>\n \n <p><i>DEPDC5</i> 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.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p><i>Depdc5</i> 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.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p><i>Depdc5</i> deletion in excitatory neurons in cortical layer 5 and dentate gyrus caused frequent generalized tonic–clonic seizures and SUDEP in young adult mice, but <i>Depdc5</i> 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.</p>\n </section>\n \n <section>\n \n <h3> Interpretation</h3>\n \n <p><i>Depdc5</i> deletion in excitatory neurons is sufficient to cause <i>DEPDC5</i>-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</p>\n </section>\n </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"94 5","pages":"812-824"},"PeriodicalIF":8.1000,"publicationDate":"2023-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.26773","citationCount":"1","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of Neurology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ana.26773","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}

引用次数: 1

Abstract

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

Abstract Image

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

癫痫猝死和DEPDC5相关癫痫小鼠模型中的呼吸缺陷。

目的：DEPDC5是伴有或不伴有皮质发育畸形的家族性局灶性癫痫的常见致病基因。其致病性变体也使癫痫（SUDEP）发生意外猝死的风险显著增加，为研究神经发育、癫痫和心肺功能的病理生理学提供了机会。迫切需要了解DEPDC5相关癫痫和SUDEP的机制，确定高危患者的生物标志物，并制定预防性干预措施。方法：在小鼠大脑的兴奋性或抑制性神经元中特异性删除Depdc5，以确定驱动癫痫发生和SUDEP的神经元亚型。进行脑电图（EEG）、心脏和呼吸记录，以确定与SUDEP相关的心肺表型。还对这些小鼠的基线呼吸功能和对缺氧挑战的反应进行了研究。结果：5层皮质和齿状回兴奋性神经元的Depdc5缺失导致年轻成年小鼠频繁的全身性强直-阵挛发作和SUDEP，而皮质中间神经元的Depdc5缺失则没有。在致命性和非致命性癫痫发作中观察到发作偏移后立即出现的脑电图抑制，但只有在致命性癫痫中才会失去低振幅节律θ频率活动。此外，这些小鼠在SUDEP之前就出现了基线呼吸功能障碍，在此期间，发作性呼吸暂停早在晚期心脏停搏之前就发生了。解释：兴奋性神经元中的Depdc5缺失足以导致Depdc5相关癫痫和SUDEP。冰呼吸暂停和呼吸失调在SUDEP中起着关键作用。我们的研究还提供了一种新的小鼠模型来研究DEPDC5相关癫痫和SUDEP的潜在机制。ANN NEUROL 2023。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Annals of Neurology 医学-临床神经学

CiteScore

18.00

自引率

1.80%

发文量

270

审稿时长

3-8 weeks

期刊介绍： Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.