Neurodevelopmental defects in Dravet syndrome Scn1a+/− mice: Targeting GABA-switch rescues behavioral dysfunctions but not seizures and mortality
Dravet syndrome (DS) is a developmental and epileptic encephalopathy (DEE) caused by mutations of the SCN1A gene (NaV1.1 sodium channel) and characterized by seizures, motor disabilities and cognitive/behavioral deficits, including autistic traits. The relative role of seizures and neurodevelopmenta...
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Elsevier
2025-04-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125000695 |
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| author | Lara Pizzamiglio Fabrizio Capitano Evgeniia Rusina Giuliana Fossati Elisabetta Menna Isabelle Léna Flavia Antonucci Massimo Mantegazza |
| author_facet | Lara Pizzamiglio Fabrizio Capitano Evgeniia Rusina Giuliana Fossati Elisabetta Menna Isabelle Léna Flavia Antonucci Massimo Mantegazza |
| author_sort | Lara Pizzamiglio |
| collection | DOAJ |
| description | Dravet syndrome (DS) is a developmental and epileptic encephalopathy (DEE) caused by mutations of the SCN1A gene (NaV1.1 sodium channel) and characterized by seizures, motor disabilities and cognitive/behavioral deficits, including autistic traits. The relative role of seizures and neurodevelopmental defects in disease progression, as well as the role of the mutation in inducing early neurodevelopmental defects before symptoms' onset, are not clear yet. A delayed switch of GABAergic transmission from excitatory to inhibitory (GABA-switch) was reported in models of DS, but its effects on the phenotype have not been investigated.Using a multi-scale approach, here we show that targeting GABA-switch with the drugs KU55933 (KU) or bumetanide (which upregulate KCC2 or inhibits NKCC1 chloride transporters, respectively) rescues social interaction deficits and reduces hyperactivity observed in P21 Scn1a+/− DS mouse model. Bumetanide also improves spatial working memory defects. Importantly, neither KU nor bumetanide have effect on seizures or mortality rate. Also, we disclose early behavioral defects and delayed neurodevelopmental milestones well before seizure onset, at the beginning of NaV1.1 expression.We thus reveal that neurodevelopmental components in DS, in particular GABA switch, underlie some cognitive/behavioral defects, but not seizures. Our work provides further evidence that seizures and neuropsychiatric dysfunctions in DEEs can be uncoupled and can have differential pathological mechanisms. They could be treated separately with targeted pharmacological strategies. |
| format | Article |
| id | doaj-art-19f81afac6f646d0b2f6e00ff9eaa816 |
| institution | DOAJ |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-19f81afac6f646d0b2f6e00ff9eaa8162025-08-20T02:55:46ZengElsevierNeurobiology of Disease1095-953X2025-04-0120710685310.1016/j.nbd.2025.106853Neurodevelopmental defects in Dravet syndrome Scn1a+/− mice: Targeting GABA-switch rescues behavioral dysfunctions but not seizures and mortalityLara Pizzamiglio0Fabrizio Capitano1Evgeniia Rusina2Giuliana Fossati3Elisabetta Menna4Isabelle Léna5Flavia Antonucci6Massimo Mantegazza7Université Côte d'Azur, Valbonne-Sophia Antipolis, France; CNRS UMR7275, Institute of Molecular and Cellular Pharmacology (IPMC), Valbonne-Sophia Antipolis, France; Inserm U1323, Valbonne-Sophia Antipolis, FranceUniversité Côte d'Azur, Valbonne-Sophia Antipolis, France; CNRS UMR7275, Institute of Molecular and Cellular Pharmacology (IPMC), Valbonne-Sophia Antipolis, France; Inserm U1323, Valbonne-Sophia Antipolis, FranceUniversité Côte d'Azur, Valbonne-Sophia Antipolis, France; CNRS UMR7275, Institute of Molecular and Cellular Pharmacology (IPMC), Valbonne-Sophia Antipolis, France; Inserm U1323, Valbonne-Sophia Antipolis, FranceIRCCS Humanitas Research Hospital, Rozzano, Milan, ItalyIRCCS Humanitas Research Hospital, Rozzano, Milan, Italy; Institute of Neuroscience - National Research Council of Italy (CNR) c/o Humanitas Mirasole S.p.A, Rozzano, Milan, ItalyUniversité Côte d'Azur, Valbonne-Sophia Antipolis, France; CNRS UMR7275, Institute of Molecular and Cellular Pharmacology (IPMC), Valbonne-Sophia Antipolis, France; Inserm U1323, Valbonne-Sophia Antipolis, FranceInstitute of Neuroscience - National Research Council of Italy (CNR) c/o Humanitas Mirasole S.p.A, Rozzano, Milan, Italy; Department of Medical Biotechnology and Translational Medicine (BIOMETRA), University of Milan, Milan, Italy; Corresponding author at: Department of Medical Biotechnology and Translational Medicine (BIOMETRA), University of Milan, Via Vanvitelli 32, 20133 Milan, Italy.Université Côte d'Azur, Valbonne-Sophia Antipolis, France; CNRS UMR7275, Institute of Molecular and Cellular Pharmacology (IPMC), Valbonne-Sophia Antipolis, France; Inserm U1323, Valbonne-Sophia Antipolis, France; Corresponding author at: Institute of Molecular and Cellular Pharmacology (IPMC), University Côte d'Azur-CNRS UMR7275-Inserm U1323, 660 Route des Lucioles, 06560 Valbonne-Sophia Antipolis, France.Dravet syndrome (DS) is a developmental and epileptic encephalopathy (DEE) caused by mutations of the SCN1A gene (NaV1.1 sodium channel) and characterized by seizures, motor disabilities and cognitive/behavioral deficits, including autistic traits. The relative role of seizures and neurodevelopmental defects in disease progression, as well as the role of the mutation in inducing early neurodevelopmental defects before symptoms' onset, are not clear yet. A delayed switch of GABAergic transmission from excitatory to inhibitory (GABA-switch) was reported in models of DS, but its effects on the phenotype have not been investigated.Using a multi-scale approach, here we show that targeting GABA-switch with the drugs KU55933 (KU) or bumetanide (which upregulate KCC2 or inhibits NKCC1 chloride transporters, respectively) rescues social interaction deficits and reduces hyperactivity observed in P21 Scn1a+/− DS mouse model. Bumetanide also improves spatial working memory defects. Importantly, neither KU nor bumetanide have effect on seizures or mortality rate. Also, we disclose early behavioral defects and delayed neurodevelopmental milestones well before seizure onset, at the beginning of NaV1.1 expression.We thus reveal that neurodevelopmental components in DS, in particular GABA switch, underlie some cognitive/behavioral defects, but not seizures. Our work provides further evidence that seizures and neuropsychiatric dysfunctions in DEEs can be uncoupled and can have differential pathological mechanisms. They could be treated separately with targeted pharmacological strategies.http://www.sciencedirect.com/science/article/pii/S0969996125000695Developmental and epileptic encephalopathyGABAEpilepsyAutismNav1.1Sodium channel |
| spellingShingle | Lara Pizzamiglio Fabrizio Capitano Evgeniia Rusina Giuliana Fossati Elisabetta Menna Isabelle Léna Flavia Antonucci Massimo Mantegazza Neurodevelopmental defects in Dravet syndrome Scn1a+/− mice: Targeting GABA-switch rescues behavioral dysfunctions but not seizures and mortality Neurobiology of Disease Developmental and epileptic encephalopathy GABA Epilepsy Autism Nav1.1 Sodium channel |
| title | Neurodevelopmental defects in Dravet syndrome Scn1a+/− mice: Targeting GABA-switch rescues behavioral dysfunctions but not seizures and mortality |
| title_full | Neurodevelopmental defects in Dravet syndrome Scn1a+/− mice: Targeting GABA-switch rescues behavioral dysfunctions but not seizures and mortality |
| title_fullStr | Neurodevelopmental defects in Dravet syndrome Scn1a+/− mice: Targeting GABA-switch rescues behavioral dysfunctions but not seizures and mortality |
| title_full_unstemmed | Neurodevelopmental defects in Dravet syndrome Scn1a+/− mice: Targeting GABA-switch rescues behavioral dysfunctions but not seizures and mortality |
| title_short | Neurodevelopmental defects in Dravet syndrome Scn1a+/− mice: Targeting GABA-switch rescues behavioral dysfunctions but not seizures and mortality |
| title_sort | neurodevelopmental defects in dravet syndrome scn1a mice targeting gaba switch rescues behavioral dysfunctions but not seizures and mortality |
| topic | Developmental and epileptic encephalopathy GABA Epilepsy Autism Nav1.1 Sodium channel |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125000695 |
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