Investigation in blood-brain barrier integrity and susceptibility to immune cell penetration in a mouse model of Dravet syndrome
Dravet Syndrome (DS) is a pediatric encephalopathy caused by mutations in Scn1a gene encoding the α1 subunit of the NaV1.1 voltage-gated sodium channel, which lead to early febrile seizures that progress to severe tonic-clonic seizures and several long-term behavioural comorbidities. In the present...
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Elsevier
2025-03-01
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| Series: | Brain, Behavior, & Immunity - Health |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666354625000134 |
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| author | Cristina Alonso Alicia García-Culebras Valentina Satta Inés Hernández-Fisac Álvaro Sierra José A. Guimaré Ignacio Lizasoain Javier Fernández-Ruiz Onintza Sagredo |
| author_facet | Cristina Alonso Alicia García-Culebras Valentina Satta Inés Hernández-Fisac Álvaro Sierra José A. Guimaré Ignacio Lizasoain Javier Fernández-Ruiz Onintza Sagredo |
| author_sort | Cristina Alonso |
| collection | DOAJ |
| description | Dravet Syndrome (DS) is a pediatric encephalopathy caused by mutations in Scn1a gene encoding the α1 subunit of the NaV1.1 voltage-gated sodium channel, which lead to early febrile seizures that progress to severe tonic-clonic seizures and several long-term behavioural comorbidities. In the present study, we have investigated whether a possible early deterioration in the blood-brain barrier (BBB) may facilitate the infiltration of immune cells to the brain parenchyma, which may contribute to these pathogenic events. In this study, conditional knock-in Scn1a-A1783V mice and their controls were used at the postnatal day (PND25): (i) to compare their levels of several immune cell populations in the bone marrow and blood; and (ii) to analyze several BBB proteins, as well as the occurrence of immune cell infiltration and endogenous immunoglobulin G (IgG) extravasation into the brain parenchyma. Our data revealed an elevation in the number of neutrophils in the blood of DS mice, but not of B- and T-cells, despite the levels of these immune cells were significantly reduced in the bone marrow. The elevated number of blood neutrophils did not apparently originate their infiltration into the hippocampus of DS mice as an immunofluorescence analysis indicated, and the same happened in B- and T-cells. However, the levels of endogenous IgG in this brain structure were significantly elevated in DS mice compared to controls, directly indicating the occurrence of extravasation into the brain parenchyma and indirectly that the BBB in DS mice may be relatively affected, a fact confirmed by the reduction in the levels of BBB-related proteins such as ZO-1 in these mice. In conclusion, our results support the occurrence of certain degree of deterioration in the BBB in DS, which may facilitate the infiltration of immune cells to the brain, then contributing to the pathogenesis in this disease. |
| format | Article |
| id | doaj-art-1b38e76e4c6d41f88afe288ea8aa8c96 |
| institution | Kabale University |
| issn | 2666-3546 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Brain, Behavior, & Immunity - Health |
| spelling | doaj-art-1b38e76e4c6d41f88afe288ea8aa8c962025-02-11T04:35:30ZengElsevierBrain, Behavior, & Immunity - Health2666-35462025-03-0144100955Investigation in blood-brain barrier integrity and susceptibility to immune cell penetration in a mouse model of Dravet syndromeCristina Alonso0Alicia García-Culebras1Valentina Satta2Inés Hernández-Fisac3Álvaro Sierra4José A. Guimaré5Ignacio Lizasoain6Javier Fernández-Ruiz7Onintza Sagredo8Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, SpainDepartamento de Biología Celular, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Unidad de Investigación Neurovascular and Instituto Universitario de Investigación en Neuroquímica, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, SpainInstituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, SpainInstituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, SpainInstituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, SpainInstituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, SpainUnidad de Investigación Neurovascular and Instituto Universitario de Investigación en Neuroquímica, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, SpainInstituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain; Corresponding author. Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University, 28040, Madrid, Spain.Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain; Corresponding author. Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University, 28040, Madrid, Spain.Dravet Syndrome (DS) is a pediatric encephalopathy caused by mutations in Scn1a gene encoding the α1 subunit of the NaV1.1 voltage-gated sodium channel, which lead to early febrile seizures that progress to severe tonic-clonic seizures and several long-term behavioural comorbidities. In the present study, we have investigated whether a possible early deterioration in the blood-brain barrier (BBB) may facilitate the infiltration of immune cells to the brain parenchyma, which may contribute to these pathogenic events. In this study, conditional knock-in Scn1a-A1783V mice and their controls were used at the postnatal day (PND25): (i) to compare their levels of several immune cell populations in the bone marrow and blood; and (ii) to analyze several BBB proteins, as well as the occurrence of immune cell infiltration and endogenous immunoglobulin G (IgG) extravasation into the brain parenchyma. Our data revealed an elevation in the number of neutrophils in the blood of DS mice, but not of B- and T-cells, despite the levels of these immune cells were significantly reduced in the bone marrow. The elevated number of blood neutrophils did not apparently originate their infiltration into the hippocampus of DS mice as an immunofluorescence analysis indicated, and the same happened in B- and T-cells. However, the levels of endogenous IgG in this brain structure were significantly elevated in DS mice compared to controls, directly indicating the occurrence of extravasation into the brain parenchyma and indirectly that the BBB in DS mice may be relatively affected, a fact confirmed by the reduction in the levels of BBB-related proteins such as ZO-1 in these mice. In conclusion, our results support the occurrence of certain degree of deterioration in the BBB in DS, which may facilitate the infiltration of immune cells to the brain, then contributing to the pathogenesis in this disease.http://www.sciencedirect.com/science/article/pii/S2666354625000134Dravet syndromeInfantile epileptic refractory syndromesSyn1-cre/Scn1aWT/A1783V miceBehavioural comorbiditiesBBB damageImmune cell infiltration |
| spellingShingle | Cristina Alonso Alicia García-Culebras Valentina Satta Inés Hernández-Fisac Álvaro Sierra José A. Guimaré Ignacio Lizasoain Javier Fernández-Ruiz Onintza Sagredo Investigation in blood-brain barrier integrity and susceptibility to immune cell penetration in a mouse model of Dravet syndrome Brain, Behavior, & Immunity - Health Dravet syndrome Infantile epileptic refractory syndromes Syn1-cre/Scn1aWT/A1783V mice Behavioural comorbidities BBB damage Immune cell infiltration |
| title | Investigation in blood-brain barrier integrity and susceptibility to immune cell penetration in a mouse model of Dravet syndrome |
| title_full | Investigation in blood-brain barrier integrity and susceptibility to immune cell penetration in a mouse model of Dravet syndrome |
| title_fullStr | Investigation in blood-brain barrier integrity and susceptibility to immune cell penetration in a mouse model of Dravet syndrome |
| title_full_unstemmed | Investigation in blood-brain barrier integrity and susceptibility to immune cell penetration in a mouse model of Dravet syndrome |
| title_short | Investigation in blood-brain barrier integrity and susceptibility to immune cell penetration in a mouse model of Dravet syndrome |
| title_sort | investigation in blood brain barrier integrity and susceptibility to immune cell penetration in a mouse model of dravet syndrome |
| topic | Dravet syndrome Infantile epileptic refractory syndromes Syn1-cre/Scn1aWT/A1783V mice Behavioural comorbidities BBB damage Immune cell infiltration |
| url | http://www.sciencedirect.com/science/article/pii/S2666354625000134 |
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