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Early EEG and behavioral alterations in Dravet mice

View ORCID ProfileSaja Fadila, Shir Quinn, Ana Turchetti Maia, Daniel Yakubovich, Karen L. Anderson, View ORCID ProfileMoran Rubinstein
doi: https://doi.org/10.1101/2020.01.13.904557
Saja Fadila
1Goldschleger Eye Research Institute, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
4Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • ORCID record for Saja Fadila
Shir Quinn
1Goldschleger Eye Research Institute, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
4Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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Ana Turchetti Maia
1Goldschleger Eye Research Institute, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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Daniel Yakubovich
2Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
3Schneider Children’s Medical Center of Israel, Petah Tikvah, Israel
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Karen L. Anderson
1Goldschleger Eye Research Institute, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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Moran Rubinstein
1Goldschleger Eye Research Institute, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
4Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
5Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
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  • For correspondence: moranrub@tauex.tau.ac.il
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Abstract

Dravet Syndrome (Dravet) is a severe childhood epileptic encephalopathy. The disease begins around the age of six months, with a febrile stage, characterized by febrile seizures with otherwise normal development. By the end of the first year of life, the disease progresses to the worsening stage, featuring recurrent intractable seizures and the appearance of additional comorbidities, including global developmental delay, cognitive deficits, hyperactivity and motor problems. Later, in early school years, Dravet reaches the stabilization stage, in which seizure burden decreases, while Dravet-associated comorbidities persist. Dravet syndrome mouse models (DS) faithfully recapitulate the three stages of the human syndrome. Here, we performed power spectral analyses of background EEG activity in DS and their wild-type (WT) littermates, demonstrating disease stage-related alterations. Specifically, while the febrile stage activity resembled that of WT mice, we observed a marked reduction in total power during the worsening stage and a smaller reduction during the stabilization stage. Moreover, low EEG power at the worsening stage correlated with increased risk for premature death, suggesting that such measurements can potentially be used as a marker for Dravet severity. With normal development at the febrile stage and the presentation of developmental delay at the worsening stage, the contribution of recurrent seizures to the emergence of Dravet-associated comorbidities is still debated. Thus, we further characterized the behavior of WT and DS mice during the different stages of Dravet. At the febrile stage, despite their normal background EEG patterns, DS mice already demonstrated motor impairment and hyperactivity in the open field, that persisted to the worsening and stabilization stages. Conversely, clear evidence for deficits in working memory emerged later in life, during the worsening stage. These results indicate that despite the mild epilepsy at the febrile stage, DS development is already altered, suggesting that the pathophysiological mechanisms governing the appearance of some Dravet behavioral comorbidities may be independent of the epileptic phenotype.

Highlights

  • Reduction in background EEG power in Dravet

  • Low EEG power correlates with the risk of premature death

  • Motor deficits and hyperactivity are evident as early as the febrile stage

  • Cognitive deficits and detection of increased anxiety begin at the worsening stage

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Posted January 14, 2020.
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Early EEG and behavioral alterations in Dravet mice
Saja Fadila, Shir Quinn, Ana Turchetti Maia, Daniel Yakubovich, Karen L. Anderson, Moran Rubinstein
bioRxiv 2020.01.13.904557; doi: https://doi.org/10.1101/2020.01.13.904557
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Early EEG and behavioral alterations in Dravet mice
Saja Fadila, Shir Quinn, Ana Turchetti Maia, Daniel Yakubovich, Karen L. Anderson, Moran Rubinstein
bioRxiv 2020.01.13.904557; doi: https://doi.org/10.1101/2020.01.13.904557

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