Generation and Characterization of the <i>Drosophila melanogaster paralytic</i> Gene Knock-Out as a Model for Dravet Syndrome
Dravet syndrome is a severe rare epileptic disease caused by mutations in the <i>SCN1A</i> gene coding for the Nav1.1 protein, a voltage-gated sodium channel alpha subunit. We have made a knock-out of the <i>paralytic</i> gene, the single <i>Drosophila melanogaster</...
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| Autores principales: | , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
MDPI AG
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/1f156631eefa4c33926b88474ef18544 |
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| Sumario: | Dravet syndrome is a severe rare epileptic disease caused by mutations in the <i>SCN1A</i> gene coding for the Nav1.1 protein, a voltage-gated sodium channel alpha subunit. We have made a knock-out of the <i>paralytic</i> gene, the single <i>Drosophila melanogaster</i> gene encoding this type of protein, by homologous recombination. These flies showed a heat-induced seizing phenotype, and sudden death in long term seizures. In addition to seizures, neuromuscular alterations were observed in climbing, flight, and walking tests. Moreover, they also manifested some cognitive alterations, such as anxiety and problems in learning. Electrophysiological analyses from larval motor neurons showed a decrease in cell capacitance and membrane excitability, while persistent sodium current increased. To detect alterations in metabolism, we performed an NMR metabolomic profiling of heads, which revealed higher levels in some amino acids, succinate, and lactate; and also an increase in the abundance of GABA, which is the main neurotransmitter implicated in Dravet syndrome. All these changes in the <i>paralytic</i> knock-out flies indicate that this is a good model for epilepsy and specifically for Dravet syndrome. This model could be a new tool to understand the pathophysiology of the disease and to find biomarkers, genetic modifiers and new treatments. |
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