Wietske van der Ent

• Moussavi, Nastaran; van der Ent, Wietske; Diallo, Drissa; Sanogo, Rokia; Malterud, Karl Egil & Esguerra, Camila V. [Show all 7 contributors for this article] (2024). Inhibition of Seizure-Like Paroxysms and Toxicity Effects of Securidaca longepedunculata Extracts and Constituents in Zebrafish Danio rerio. ACS Chemical Neuroscience. ISSN 1948-7193. 15(3), p. 617–628. doi: 10.1021/acschemneuro.3c00642.
• Desalegn, Anteneh Assefa; van der Ent, Wietske; Lenters, Virissa Claire; Torcelino-Iszatt, Nina Louise; Stigum, Hein & Lyche, Jan Ludvig [Show all 10 contributors for this article] (2023). Perinatal exposure to potential endocrine disrupting chemicals and autism spectrum disorder: From Norwegian birth cohort to zebrafish studies. Environment International. ISSN 0160-4120. 181. doi: 10.1016/j.envint.2023.108271. Full text in Research Archive
• Skiba, Adrianna; Kozioł, Ewelina; Luca, Simon Vlad; Budzyńska, Barbara; Podlasz, Piotr & van der Ent, Wietske [Show all 12 contributors for this article] (2023). Evaluation of the Antiseizure Activity of Endemic Plant Halfordia kendack Guillaumin and Its Main Constituent, Halfordin, on a Zebrafish Pentylenetetrazole (PTZ)-Induced Seizure Model. International Journal of Molecular Sciences. ISSN 1661-6596. 24(3). doi: 10.3390/ijms24032598. Full text in Research Archive
• Silvennoinen, Katri; Gawel, Kinga Aurelia; Tsortouktzidis, Despina; Pitsch, Julika; Alhusaini, Saud & van Loo, Karen M. J. [Show all 26 contributors for this article] (2022). SCN1A overexpression, associated with a genomic region marked by a risk variant for a common epilepsy, raises seizure susceptibility. Acta Neuropathologica. ISSN 0001-6322. 144(1), p. 107–127. doi: 10.1007/s00401-022-02429-0. Full text in Research Archive
• Gawel, Kinga Aurelia; Turski, Waldemar A.; van der Ent, Wietske; Mathai, Benan John; Kirstein-Smardzewska, Karolina Joanna & Simonsen, Anne [Show all 7 contributors for this article] (2020). Phenotypic Characterization of Larval Zebrafish (Danio rerio) with Partial Knockdown of the cacna1a Gene. Molecular Neurobiology. ISSN 0893-7648. 57(4). doi: 10.1007/s12035-019-01860-x. Show summary

  The CACNA1A gene encodes the pore-forming α1 subunit of voltage-gated P/Q type Ca2+ channels (Cav2.1). Mutations in this gene, among others, have been described in patients and rodents suffering from absence seizures and episodic ataxia type 2 with/without concomitant seizures. In this study, we aimed for the first time to assess phenotypic and behavioral alterations in larval zebrafish with partial cacna1aa knockdown, placing special emphasis on changes in epileptiform-like electrographic discharges in larval brains. Whole-mount in situ hybridization analysis revealed expression of cacna1aa in the optic tectum and medulla oblongata of larval zebrafish at 4 and 5 days post-fertilization. Next, microinjection of two antisense morpholino oligomers (individually or in combination) targeting all splice variants of cacna1aa into fertilized zebrafish eggs resulted in dose-dependent mortality and decreased or absent touch response. Over 90% knockdown of cacna1aa on protein level induced epileptiform-like discharges in the optic tectum of larval zebrafish brains. Incubation of morphants with antiseizure drugs (sodium valproate, ethosuximide, lamotrigine, topiramate) significantly decreased the number and, in some cases, cumulative duration of epileptiform-like discharges. In this context, sodium valproate seemed to be the least effective. Carbamazepine did not affect the number and duration of epileptiform-like discharges. Altogether, our data indicate that cacna1aa loss-of-function zebrafish may be considered a new model of absence epilepsy and may prove useful both for the investigation of Cacna1a-mediated epileptogenesis and for in vivo drug screening.

• Tiraboschi, Ettore; Martina, Silvia; van der Ent, Wietske; Grzyb, Kamil; Gawel, Kinga Aurelia & Cordero-Maldonado, Maria Lorena [Show all 14 contributors for this article] (2020). New insights into the early mechanisms of epileptogenesis in a zebrafish model of Dravet syndrome. Epilepsia. ISSN 0013-9580. 61(3), p. 549–560. doi: 10.1111/epi.16456. Full text in Research Archive Show summary

  Abstract Objective: To pinpoint the earliest cellular defects underlying seizure onset (epileptogenic period) during perinatal brain development in a new zebrafish model of Dravet syndrome (DS) and to investigate potential disease-modifying activity of the 5HT2 receptor agonist fenfluramine. Methods: We used CRISPR/Cas9 mutagenesis to introduce a missense mutation, designed to perturb ion transport function in all channel isoforms, into scn1lab, the zebrafish orthologue of SCN1A (encoding voltage-gated sodium channel alpha subunit 1). We performed behavioral analysis and electroencephalographic recordings to measure convulsions and epileptiform discharges, followed by single-cell RNA-Seq, morphometric analysis of transgenic reporter-labeled γ-aminobutyric acidergic (GABAergic) neurons, and pharmacological profiling of mutant larvae. Results: Homozygous mutant (scn1labmut/mut ) larvae displayed spontaneous seizures with interictal, preictal, and ictal discharges (mean = 7.5 per 20-minute recording; P < .0001; one-way analysis of variance). Drop-Seq analysis revealed a 2:1 shift in the ratio of glutamatergic to GABAergic neurons in scn1labmut/mut larval brains versus wild type (WT), with dynamic changes in neuronal, glial, and progenitor cell populations. To explore disease pathophysiology further, we quantified dendritic arborization in GABAergic neurons and observed a 40% reduction in arbor number compared to WT (P < .001; n = 15 mutant, n = 16 WT). We postulate that the significant reduction in inhibitory arbors causes an inhibitory to excitatory neurotransmitter imbalance that contributes to seizures and enhanced electrical brain activity in scn1labmut/mut larvae (high-frequency range), with subsequent GABAergic neuronal loss and astrogliosis. Chronic fenfluramine administration completely restored dendritic arbor numbers to normal in scn1labmut/mut larvae, whereas similar treatment with the benzodiazepine diazepam attenuated seizures, but was ineffective in restoring neuronal cytoarchitecture. BrdU labeling revealed cell overproliferation in scn1labmut/mut larval brains that were rescued by fenfluramine but not diazepam. Significance: Our findings provide novel insights into early mechanisms of DS pathogenesis, describe dynamic cell population changes in the scn1labmut/mut brain, and present first-time evidence for potential disease modification by fenfluramine. Keywords: Dravet syndrome; epileptogenesis; fenfluramine; sodium channel; zebrafish.

• Gawel, Kinga Aurelia; Kukula-Koch, Wirginia; Nieoczym, Dorota; Stępnik, Katarzyna; van der Ent, Wietske & Banono, Nancy Saana [Show all 9 contributors for this article] (2020). The Influence of Palmatine Isolated from Berberis sibirica Radix on Pentylenetetrazole-Induced Seizures in Zebrafish. Cells. ISSN 2073-4409. 9(5). doi: 10.3390/cells9051233. Full text in Research Archive Show summary

  Palmatine (PALM) and berberine (BERB) are widely identified isoquinoline alkaloids among the representatives of the Berberidaceae botanical family. The antiseizure activity of BERB was shown previously in experimental epilepsy models. We assessed the effect of PALM in a pentylenetetrazole (PTZ)-induced seizure assay in zebrafish, with BERB as an active reference compound. Both alkaloids were isolated from the methanolic root extract of Berberis sibirica by counter-current chromatography, and their ability to cross the blood-brain barrier was determined via quantitative structure-activity relationship assay. PALM exerted antiseizure activity, as confirmed by electroencephalographic analysis, and decreased c-fos and bdnf levels in PTZ-treated larvae. In a behavioral assay, PALM dose-dependently decreased PTZ-induced hyperlocomotion. The combination of PALM and BERB in ED16 doses revealed hyperadditive activity towards PTZ-induced hyperlocomotion. Notably, we have indicated that both alkaloids may exert their anticonvulsant activity through different mechanisms of action. Additionally, the combination of both alkaloids in a 1:2.17 ratio (PALM: BERB) mimicked the activity of the pure extract, which indicates that these two active compounds are responsible for its anticonvulsive activity. In conclusion, our study reveals for the first time the anticonvulsant activity of PALM and suggests the combination of PALM and BERB may have higher therapeutic value than separate usage of these compounds.

• Gawel, Kinga Aurelia; Langlois, Melanie; Martins, Teresa G.; van der Ent, Wietske; Tiraboschi, Ettore & Jacmin, Maxime [Show all 8 contributors for this article] (2020). Seizing the moment: Zebrafish epilepsy models. Neuroscience and Biobehavioral Reviews. ISSN 0149-7634. 116, p. 1–20. doi: 10.1016/j.neubiorev.2020.06.010. Full text in Research Archive
• Gawel, Kinga Aurelia; Turski, Waldemar A.; van der Ent, Wietske; Mathai, Benan John; Kirstein-Smardzewska, Karolina Joanna & Simonsen, Anne [Show all 7 contributors for this article] (2019). Phenotypic Characterization of Larval Zebrafish (Danio rerio) with Partial Knockdown of the cacna1a Gene . Molecular Neurobiology. ISSN 0893-7648. doi: 10.1007/s12035-019-01860-x. Full text in Research Archive

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• Banono, Nancy Saana; Gawel, Kinga Aurelia; Mäki-Marttunen, Tuomo; van der Ent, Wietske; Kukula-Koch, Wirginia & Fyhn, Marianne [Show all 10 contributors for this article] (2023). Novel zebrafish model for studying neurodevelopment in Timothy syndrome.
• van der Ent, Wietske; Kirstein-Smardzewska, Karolina Joanna; Gawel, Kinga Aurelia; Banono, Nancy Saana; Eggesbø, Merete Åse & Esguerra, Camila Vicencio (2023). Evaluation of Developmental Neurotoxicity in Zebrafish (Danio rerio) by Endocrine Disrupting Chemical β-HCH.
• van der Ent, Wietske; Kirstein-Smardzewska, Karolina Joanna; Gawel, Kinga Aurelia; Banono, Nancy Saana; Eggesbø, Merete Åse & Esguerra, Camila Vicencio (2023). Evaluation of Developmental Neurotoxicity in Zebrafish (Danio rerio) by Endocrine Disrupting Chemical β-HCH.
• Banono, Nancy Saana; van der Ent, Wietske; Gawel, Kinga Aurelia; Marttunen, Tuomo; Kukula, Wirginia Koch & Fyhn, Marianne [Show all 9 contributors for this article] (2022). Zebrafish larvae with cacna1c mutations display both shared and distinct phenotypes.
• van der Ent, Wietske (2022). Modelling SNAREopathies in Zebrafish.
• van der Ent, Wietske (2022). Toward novel therapeutic interventions for rare pediatric epilepsies.
• van der Ent, Wietske (2022). Toward novel therapeutic interventions for rare pediatric epilepsies.
• Banono, Nancy Saana; van der Ent, Wietske; Gawel, Kinga Aurelia; Mäki-Marttunen, Tuomo; Kukula-Koch, Wirginia & Einevoll, Gaute [Show all 9 contributors for this article] (2021). Functional characterisation of cacna1c mutations in zebrafish larvae.

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