A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients
Dravet Syndrome is an intractable form of childhood epilepsy associated with deleterious mutations in SCN1A, the gene encoding neuronal sodium channel Nav1.1. Earlier studies using human induced pluripotent stem cells (iPSCs) have produced mixed results regarding the importance of Nav1.1 in human in...
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2016-07-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/13073 |
| _version_ | 1811236827802107904 |
|---|---|
| author | Yishan Sun Sergiu P Paşca Thomas Portmann Carleton Goold Kathleen A Worringer Wendy Guan Karen C Chan Hui Gai Daniel Vogt Ying-Jiun J Chen Rong Mao Karrie Chan John LR Rubenstein Daniel V Madison Joachim Hallmayer Wendy M Froehlich-Santino Jonathan A Bernstein Ricardo E Dolmetsch |
| author_facet | Yishan Sun Sergiu P Paşca Thomas Portmann Carleton Goold Kathleen A Worringer Wendy Guan Karen C Chan Hui Gai Daniel Vogt Ying-Jiun J Chen Rong Mao Karrie Chan John LR Rubenstein Daniel V Madison Joachim Hallmayer Wendy M Froehlich-Santino Jonathan A Bernstein Ricardo E Dolmetsch |
| author_sort | Yishan Sun |
| collection | DOAJ |
| description | Dravet Syndrome is an intractable form of childhood epilepsy associated with deleterious mutations in SCN1A, the gene encoding neuronal sodium channel Nav1.1. Earlier studies using human induced pluripotent stem cells (iPSCs) have produced mixed results regarding the importance of Nav1.1 in human inhibitory versus excitatory neurons. We studied a Nav1.1 mutation (p.S1328P) identified in a pair of twins with Dravet Syndrome and generated iPSC-derived neurons from these patients. Characterization of the mutant channel revealed a decrease in current amplitude and hypersensitivity to steady-state inactivation. We then differentiated Dravet-Syndrome and control iPSCs into telencephalic excitatory neurons or medial ganglionic eminence (MGE)-like inhibitory neurons. Dravet inhibitory neurons showed deficits in sodium currents and action potential firing, which were rescued by a Nav1.1 transgene, whereas Dravet excitatory neurons were normal. Our study identifies biophysical impairments underlying a deleterious Nav1.1 mutation and supports the hypothesis that Dravet Syndrome arises from defective inhibitory neurons. |
| first_indexed | 2024-04-12T12:15:55Z |
| format | Article |
| id | doaj.art-9e56d9a7d51d450d935655ce1d73145f |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:15:55Z |
| publishDate | 2016-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-9e56d9a7d51d450d935655ce1d73145f2022-12-22T03:33:26ZengeLife Sciences Publications LtdeLife2050-084X2016-07-01510.7554/eLife.13073A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patientsYishan Sun0Sergiu P Paşca1Thomas Portmann2Carleton Goold3Kathleen A Worringer4Wendy Guan5Karen C Chan6Hui Gai7Daniel Vogt8Ying-Jiun J Chen9Rong Mao10Karrie Chan11John LR Rubenstein12Daniel V Madison13Joachim Hallmayer14Wendy M Froehlich-Santino15Jonathan A Bernstein16Ricardo E Dolmetsch17https://orcid.org/0000-0002-2738-8338Novartis Institutes for BioMedical Research, Cambridge, United States; Department of Neurobiology, Stanford University School of Medicine, Stanford, United StatesDepartment of Neurobiology, Stanford University School of Medicine, Stanford, United States; Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, United StatesDepartment of Neurobiology, Stanford University School of Medicine, Stanford, United StatesNovartis Institutes for BioMedical Research, Cambridge, United States; Department of Neurobiology, Stanford University School of Medicine, Stanford, United StatesNovartis Institutes for BioMedical Research, Cambridge, United StatesNovartis Institutes for BioMedical Research, Cambridge, United StatesDepartment of Neurobiology, Stanford University School of Medicine, Stanford, United StatesDepartment of Neurobiology, Stanford University School of Medicine, Stanford, United StatesDepartment of Psychiatry, University of California, San Francisco, San Francisco, United StatesDepartment of Psychiatry, University of California, San Francisco, San Francisco, United StatesDepartment of Neurobiology, Stanford University School of Medicine, Stanford, United StatesNovartis Institutes for BioMedical Research, Cambridge, United StatesDepartment of Psychiatry, University of California, San Francisco, San Francisco, United StatesDepartment of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, United StatesDepartment of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, United StatesDepartment of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, United StatesDepartment of Pediatrics, Division of Genetics, Stanford University School of Medicine, Stanford, United StatesNovartis Institutes for BioMedical Research, Cambridge, United States; Department of Neurobiology, Stanford University School of Medicine, Stanford, United StatesDravet Syndrome is an intractable form of childhood epilepsy associated with deleterious mutations in SCN1A, the gene encoding neuronal sodium channel Nav1.1. Earlier studies using human induced pluripotent stem cells (iPSCs) have produced mixed results regarding the importance of Nav1.1 in human inhibitory versus excitatory neurons. We studied a Nav1.1 mutation (p.S1328P) identified in a pair of twins with Dravet Syndrome and generated iPSC-derived neurons from these patients. Characterization of the mutant channel revealed a decrease in current amplitude and hypersensitivity to steady-state inactivation. We then differentiated Dravet-Syndrome and control iPSCs into telencephalic excitatory neurons or medial ganglionic eminence (MGE)-like inhibitory neurons. Dravet inhibitory neurons showed deficits in sodium currents and action potential firing, which were rescued by a Nav1.1 transgene, whereas Dravet excitatory neurons were normal. Our study identifies biophysical impairments underlying a deleterious Nav1.1 mutation and supports the hypothesis that Dravet Syndrome arises from defective inhibitory neurons.https://elifesciences.org/articles/13073Dravet SyndromeNaV1.1SCN1AiPSCinterneurons |
| spellingShingle | Yishan Sun Sergiu P Paşca Thomas Portmann Carleton Goold Kathleen A Worringer Wendy Guan Karen C Chan Hui Gai Daniel Vogt Ying-Jiun J Chen Rong Mao Karrie Chan John LR Rubenstein Daniel V Madison Joachim Hallmayer Wendy M Froehlich-Santino Jonathan A Bernstein Ricardo E Dolmetsch A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients eLife Dravet Syndrome NaV1.1 SCN1A iPSC interneurons |
| title | A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients |
| title_full | A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients |
| title_fullStr | A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients |
| title_full_unstemmed | A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients |
| title_short | A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients |
| title_sort | deleterious nav1 1 mutation selectively impairs telencephalic inhibitory neurons derived from dravet syndrome patients |
| topic | Dravet Syndrome NaV1.1 SCN1A iPSC interneurons |
| url | https://elifesciences.org/articles/13073 |
| work_keys_str_mv | AT yishansun adeleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT sergiuppasca adeleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT thomasportmann adeleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT carletongoold adeleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT kathleenaworringer adeleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT wendyguan adeleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT karencchan adeleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT huigai adeleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT danielvogt adeleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT yingjiunjchen adeleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT rongmao adeleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT karriechan adeleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT johnlrrubenstein adeleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT danielvmadison adeleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT joachimhallmayer adeleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT wendymfroehlichsantino adeleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT jonathanabernstein adeleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT ricardoedolmetsch adeleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT yishansun deleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT sergiuppasca deleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT thomasportmann deleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT carletongoold deleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT kathleenaworringer deleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT wendyguan deleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT karencchan deleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT huigai deleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT danielvogt deleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT yingjiunjchen deleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT rongmao deleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT karriechan deleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT johnlrrubenstein deleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT danielvmadison deleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT joachimhallmayer deleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT wendymfroehlichsantino deleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT jonathanabernstein deleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients AT ricardoedolmetsch deleteriousnav11mutationselectivelyimpairstelencephalicinhibitoryneuronsderivedfromdravetsyndromepatients |