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| DOI | Trouver le DOI : https://doi.org/10.1534/genetics.120.303399 |
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| Auteur | Rechercher : Dyment, David A.; Rechercher : Schock, Sarah C.; Rechercher : Deloughery, Kristen; Rechercher : Tran, Minh Hieu; Rechercher : Ure, Kerstin; Rechercher : Nutter, Lauryl M. J.; Rechercher : Creighton, Amie; Rechercher : Yuan, Julie; Rechercher : Banderali, Umberto1; Rechercher : Comas, Tanya1; Rechercher : Baumann, Ewa1; Rechercher : Jezierski, Anna1; Rechercher : Boycott, Kym M.; Rechercher : Mackenzie, Alex E.; Rechercher : Martina, Marzia1 |
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| Affiliation | - Conseil national de recherches du Canada. Thérapeutique en santé humaine
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| Format | Texte, Article |
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| Sujet | Dravet syndrome; induced neurons; pyramidal cells; interneurons; CA1; hippocampus; sodium current; mouse model |
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| Résumé | Dravet syndrome is a developmental epileptic encephalopathy caused by pathogenic variation in SCN1A. To characterize the pathogenic substitution (p.H939R) of a local individual with Dravet syndrome, fibroblast cells from the individual were reprogrammed to pluripotent stem cells and differentiated into neurons. Sodium currents of these neurons were compared with healthy control induced neurons. A novel Scn1aᴴ⁹³⁹ᴿ/⁺ mouse model was generated with the p.H939R substitution. Immunohistochemistry and electrophysiological experiments were performed on hippocampal slices of Scn1aᴴ⁹³⁹ᴿ/⁺ mice. We found that the sodium currents recorded in the proband-induced neurons were significantly smaller and slower compared to wild type (WT). The resting membrane potential and spike amplitude were significantly depolarized in the proband-induced neurons. Similar differences in resting membrane potential and spike amplitude were observed in the interneurons of the hippocampus of Scn1aᴴ⁹³⁹ᴿ/⁺ mice. The Scn1aᴴ⁹³⁹ᴿ/⁺ mice showed the characteristic features of a Dravet-like phenotype: increased mortality and both spontaneous and heat-induced seizures. Immunohistochemistry showed a reduction in amount of parvalbumin and vesicular acetylcholine transporter in the hippocampus of Scn1aᴴ⁹³⁹ᴿ/⁺ compared to WT mice. Overall, these results underline hyper-excitability of the hippocampal CA1 circuit of this novel mouse model of Dravet syndrome which, under certain conditions, such as temperature, can trigger seizure activity. This hyper-excitability is due to the altered electrophysiological properties of pyramidal neurons and interneurons which are caused by the dysfunction of the sodium channel bearing the p.H939R substitution. This novel Dravet syndrome model also highlights the reduction in acetylcholine and the contribution of pyramidal cells, in addition to interneurons, to network hyper-excitability. |
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| Date de publication | 2020-06-17 |
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| Maison d’édition | Genetics Society of America |
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| Dans | |
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| Supplément au titre | |
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| Langue | anglais |
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| Publications évaluées par des pairs | Oui |
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| Numéro du CNRC | NRC-HHT-53492 |
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| Exporter la notice | Exporter en format RIS |
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| Signaler une correction | Signaler une correction (s'ouvre dans un nouvel onglet) |
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| Identificateur de l’enregistrement | 709e6445-ebcb-4187-a04f-2b79e0079020 |
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| Enregistrement créé | 2020-10-01 |
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| Enregistrement modifié | 2020-10-01 |
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