A novel rat model of Dravet syndrome recapitulates clinical hallmarks
Dravet syndrome (DS) is a debilitating infantile epileptic encephalopathy characterized by seizures induced by high body temperature (hyperthermia), sudden unexpected death in epilepsy (SUDEP), cognitive impairment, and behavioral disturbances. The most common cause of DS is haploinsufficiency of th...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-08-01
|
| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996123002085 |
| _version_ | 1797755840491421696 |
|---|---|
| author | Miao Li Lixin Yang Weixin Qian Saikat Ray Zhonghua Lu Tao Liu Ying-Ying Zou Robert K. Naumann Hong Wang |
| author_facet | Miao Li Lixin Yang Weixin Qian Saikat Ray Zhonghua Lu Tao Liu Ying-Ying Zou Robert K. Naumann Hong Wang |
| author_sort | Miao Li |
| collection | DOAJ |
| description | Dravet syndrome (DS) is a debilitating infantile epileptic encephalopathy characterized by seizures induced by high body temperature (hyperthermia), sudden unexpected death in epilepsy (SUDEP), cognitive impairment, and behavioral disturbances. The most common cause of DS is haploinsufficiency of the SCN1A gene, which encodes the voltage-gated sodium channel Nav1.1. In current mouse models of DS, the epileptic phenotype is strictly dependent on the genetic background and most mouse models exhibit drastically higher SUDEP rates than patients. Therefore, we sought to develop an alternative animal model for DS. Here, we report the generation and characterization of a Scn1a halploinsufficiency rat model of DS by disrupting the Scn1a allele. Scn1a+/− rats show reduced Scn1a expression in the cerebral cortex, hippocampus and thalamus. Homozygous null rats die prematurely. Heterozygous animals are highly susceptible to heat-induced seizures, the clinical hallmark of DS, but are otherwise normal in survival, growth, and behavior without seizure induction. Hyperthermia-induced seizures activate distinct sets of neurons in the hippocampus and hypothalamus in Scn1a+/− rats. Electroencephalogram (EEG) recordings in Scn1a+/− rats reveal characteristic ictal EEG with high amplitude bursts with significantly increased delta and theta power. After the initial hyperthermia-induced seizures, non-convulsive, and convulsive seizures occur spontaneously in Scn1a+/− rats. In conclusion, we generate a Scn1a haploinsufficiency rat model with phenotypes closely resembling DS, providing a unique platform for establishing therapies for DS. |
| first_indexed | 2024-03-12T17:51:51Z |
| format | Article |
| id | doaj.art-b97d471372094aebbcdee1a48399f6e9 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-03-12T17:51:51Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-b97d471372094aebbcdee1a48399f6e92023-08-03T04:22:44ZengElsevierNeurobiology of Disease1095-953X2023-08-01184106193A novel rat model of Dravet syndrome recapitulates clinical hallmarksMiao Li0Lixin Yang1Weixin Qian2Saikat Ray3Zhonghua Lu4Tao Liu5Ying-Ying Zou6Robert K. Naumann7Hong Wang8The Brain Cognition and Brain Disease Institute, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; CAS Key Laboratory of Brain Connectome and Manipulation, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaThe Brain Cognition and Brain Disease Institute, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; CAS Key Laboratory of Brain Connectome and Manipulation, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaThe Brain Cognition and Brain Disease Institute, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaDepartment of Brain Sciences, Weizmann Institute of Science, Rehovot, IsraelThe Brain Cognition and Brain Disease Institute, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; CAS Key Laboratory of Brain Connectome and Manipulation, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaState Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.Department of Pathology and Pathophysiology, Faculty of Basic Medical Sciences, Kunming Medical University, Kunming, ChinaThe Brain Cognition and Brain Disease Institute, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; CAS Key Laboratory of Brain Connectome and Manipulation, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China; Corresponding authors at: The Brain Cognition and Brain Disease Institute, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.The Brain Cognition and Brain Disease Institute, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; CAS Key Laboratory of Brain Connectome and Manipulation, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China; Shenzhen Key Laboratory of Drug Addiction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China; Corresponding authors at: The Brain Cognition and Brain Disease Institute, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.Dravet syndrome (DS) is a debilitating infantile epileptic encephalopathy characterized by seizures induced by high body temperature (hyperthermia), sudden unexpected death in epilepsy (SUDEP), cognitive impairment, and behavioral disturbances. The most common cause of DS is haploinsufficiency of the SCN1A gene, which encodes the voltage-gated sodium channel Nav1.1. In current mouse models of DS, the epileptic phenotype is strictly dependent on the genetic background and most mouse models exhibit drastically higher SUDEP rates than patients. Therefore, we sought to develop an alternative animal model for DS. Here, we report the generation and characterization of a Scn1a halploinsufficiency rat model of DS by disrupting the Scn1a allele. Scn1a+/− rats show reduced Scn1a expression in the cerebral cortex, hippocampus and thalamus. Homozygous null rats die prematurely. Heterozygous animals are highly susceptible to heat-induced seizures, the clinical hallmark of DS, but are otherwise normal in survival, growth, and behavior without seizure induction. Hyperthermia-induced seizures activate distinct sets of neurons in the hippocampus and hypothalamus in Scn1a+/− rats. Electroencephalogram (EEG) recordings in Scn1a+/− rats reveal characteristic ictal EEG with high amplitude bursts with significantly increased delta and theta power. After the initial hyperthermia-induced seizures, non-convulsive, and convulsive seizures occur spontaneously in Scn1a+/− rats. In conclusion, we generate a Scn1a haploinsufficiency rat model with phenotypes closely resembling DS, providing a unique platform for establishing therapies for DS.http://www.sciencedirect.com/science/article/pii/S0969996123002085Dravet syndromeRatScn1aEpilepsyHyperthermia-induced seizureEEG |
| spellingShingle | Miao Li Lixin Yang Weixin Qian Saikat Ray Zhonghua Lu Tao Liu Ying-Ying Zou Robert K. Naumann Hong Wang A novel rat model of Dravet syndrome recapitulates clinical hallmarks Neurobiology of Disease Dravet syndrome Rat Scn1a Epilepsy Hyperthermia-induced seizure EEG |
| title | A novel rat model of Dravet syndrome recapitulates clinical hallmarks |
| title_full | A novel rat model of Dravet syndrome recapitulates clinical hallmarks |
| title_fullStr | A novel rat model of Dravet syndrome recapitulates clinical hallmarks |
| title_full_unstemmed | A novel rat model of Dravet syndrome recapitulates clinical hallmarks |
| title_short | A novel rat model of Dravet syndrome recapitulates clinical hallmarks |
| title_sort | novel rat model of dravet syndrome recapitulates clinical hallmarks |
| topic | Dravet syndrome Rat Scn1a Epilepsy Hyperthermia-induced seizure EEG |
| url | http://www.sciencedirect.com/science/article/pii/S0969996123002085 |
| work_keys_str_mv | AT miaoli anovelratmodelofdravetsyndromerecapitulatesclinicalhallmarks AT lixinyang anovelratmodelofdravetsyndromerecapitulatesclinicalhallmarks AT weixinqian anovelratmodelofdravetsyndromerecapitulatesclinicalhallmarks AT saikatray anovelratmodelofdravetsyndromerecapitulatesclinicalhallmarks AT zhonghualu anovelratmodelofdravetsyndromerecapitulatesclinicalhallmarks AT taoliu anovelratmodelofdravetsyndromerecapitulatesclinicalhallmarks AT yingyingzou anovelratmodelofdravetsyndromerecapitulatesclinicalhallmarks AT robertknaumann anovelratmodelofdravetsyndromerecapitulatesclinicalhallmarks AT hongwang anovelratmodelofdravetsyndromerecapitulatesclinicalhallmarks AT miaoli novelratmodelofdravetsyndromerecapitulatesclinicalhallmarks AT lixinyang novelratmodelofdravetsyndromerecapitulatesclinicalhallmarks AT weixinqian novelratmodelofdravetsyndromerecapitulatesclinicalhallmarks AT saikatray novelratmodelofdravetsyndromerecapitulatesclinicalhallmarks AT zhonghualu novelratmodelofdravetsyndromerecapitulatesclinicalhallmarks AT taoliu novelratmodelofdravetsyndromerecapitulatesclinicalhallmarks AT yingyingzou novelratmodelofdravetsyndromerecapitulatesclinicalhallmarks AT robertknaumann novelratmodelofdravetsyndromerecapitulatesclinicalhallmarks AT hongwang novelratmodelofdravetsyndromerecapitulatesclinicalhallmarks |