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Research ArticleResearch Article: Negative Results, Disorders of the Nervous System

Investigation of MicroRNA-134 as a Target against Seizures and SUDEP in a Mouse Model of Dravet Syndrome

Rogério R. Gerbatin, Joana Augusto, Gareth Morris, Aoife Campbell, Jesper Worm, Elena Langa, Cristina R. Reschke and David C. Henshall
eNeuro 9 September 2022, 9 (5) ENEURO.0112-22.2022; DOI: https://doi.org/10.1523/ENEURO.0112-22.2022
Rogério R. Gerbatin
1Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
2FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
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Joana Augusto
1Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
4Department of Physiology, Faculty of Medicine, Trinity College Dublin, Dublin, D02 PN40, Ireland
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Gareth Morris
1Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
2FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
5Department of Neuroscience, Physiology and Pharmacology, University College London, London, WC1E 6BT, United Kingdom
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Aoife Campbell
1Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
2FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
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Jesper Worm
6Roche Innovation Center Copenhagen, Copenhagen, CH-4070, Denmark
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Elena Langa
1Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
2FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
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Cristina R. Reschke
1Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
2FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
3School of Pharmacy and Biomedical Sciences, RCSI University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
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David C. Henshall
1Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
2FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
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  • Figure 1.
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    Figure 1.

    Ant-134 dose response curve on hyperthermia-induced seizures in F1.Scn1a(+/−)tm1kea mice. A, At P17, mice were weaned and intracerebroventricularly injected with 0.1, 0.5, or 1 nmol dose of Ant-134 or scr. At P18, hyperthermia challenge was induced by placing the animals in a thermostat-controlled heating chamber. Graphs show the temperature threshold for mice to develop a seizure (B), median duration of seizures (C), and the respective seizure severity according to a modified Racine scale (D). E, Transcript levels of miR-134 in the ipsilateral hippocampus 24 h after scr or Ant-134 injections. F–I, Expression of validated targets of miR-134 (Limk1, Creb1, and Dcx) and Scn1a levels in scr or Ant-134-treated mice. B–D, Kruskal–Wallis test, median IQR. E–I, One-way ANOVA, mean (SD). **p < 0.01, ***p < 0.001, ****p < 0.0001. One outlier from Ant-134 F1.Scn1a(+/−)tm1kea-treated mice group was removed according to Grubbs’ test (α = 0.01) in Dcx transcript levels. Representative images of intracerebroventricular injections with methylene blue in P21 mice can be found in Extended Data Figure 1-1. Relative expression of miR-134, its validated targets (Limk1, Creb1, and Dcx) and Scn1a levels in cortical tissue can be found in Extended Data Figure 1-2.

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    Figure 2.

    Ant-134 0.1 nmol does not prevent SRS and SUDEP occurrence in F1.Scn1a(+/−)tm1kea mice. A, Schematic showing the experimental design used to investigate the occurrence of SRS, SUDEP and miR-134 levels in F1.Scn1a(+/−)tm1kea mice during the worsening stage of DS. B, Representation of the frequency of SRS experienced by scr and Ant-134 F1.Scn1a(+/−)tm1kea-treated mice according to a color scale ranging from 0 to 10 seizures or more. C, Quantitative analyses of SRS between P21 and P28. D, E, Seizure duration and severity in Ant-134-treated mice compared with scr. F, SUDEP rates between scr and Ant-134 F1.Scn1a(+/−)tm1kea-treated mice. G, Taqman results confirming Ant-134 0.1 nmol produced a knock-down in miR-134 levels when compared with scr mice. H, I, EEG representative trace of SRS in scr and Ant-134 F1.Scn1a(+/−)tm1kea-treated mice. (n = 6/group). C, D, Student’s t test, mean (SD). E, G, Mann–Whitney test, median IQR. F, log-rank test. **p < 0.01.

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    Table 1

    Statistical table showing the relevant information related to each statistical test performed

    ExperimentData structureType of testPower
    Fig. 1B–DTemperature threshold, Seizure duration
    and Racine scale, respectively
    Non-normal distributionKruskal–Wallis test95%
    Fig. 1E–I and
    Extended Data Fig. 1-2
    miR-134, Limk1, Creb1, Dcx, and scn1a
    relative expression, respectively
    Normal distributionOne-way ANOVA95%
    Fig. 2C,DNumber of seizure and seizure durationNormal distributionStudent’s t test95%
    Fig. 2E,GRacine scale and miR-134Non-normal distributionMann–Whitney test95%
    Fig. 2F% SurvivalNon-normal distributionlog-rank test95%

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  • Extended Data Figure 1-1

    Representative images of intracerebroventricular injections in P21 mice. Methylene blue into the ventricles of (A) male and (B) female P21 mice. Download Figure 1-1, TIF file.

  • Extended Data Figure 1-2

    Ant-134 0.1nmol effect on miR-134, Limk1, Creb1, Dcx and Scn1a expression in the ipsilateral cortex of F1.Scn1a(+/-)tm1kea mice. A, Graph shows the miR-134 levels in the ipsilateral cortex and (B–E) the expression of validated targets of miR-134 Limk1, Creb1 and Dcx and the respective Scn1a levels ∼24 hrs after scr or Ant-134 0.1nmol intracerebroventricular injections. A–E, One-way ANOVA, mean (SD); **p < 0.01, ****p < 0.0001. Download Figure 1-2, TIF file.

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Investigation of MicroRNA-134 as a Target against Seizures and SUDEP in a Mouse Model of Dravet Syndrome
Rogério R. Gerbatin, Joana Augusto, Gareth Morris, Aoife Campbell, Jesper Worm, Elena Langa, Cristina R. Reschke, David C. Henshall
eNeuro 9 September 2022, 9 (5) ENEURO.0112-22.2022; DOI: 10.1523/ENEURO.0112-22.2022

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Investigation of MicroRNA-134 as a Target against Seizures and SUDEP in a Mouse Model of Dravet Syndrome
Rogério R. Gerbatin, Joana Augusto, Gareth Morris, Aoife Campbell, Jesper Worm, Elena Langa, Cristina R. Reschke, David C. Henshall
eNeuro 9 September 2022, 9 (5) ENEURO.0112-22.2022; DOI: 10.1523/ENEURO.0112-22.2022
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Keywords

  • Dravet syndrome
  • miR-134
  • Oligonucleotides
  • seizure
  • SUDEP

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