دورية أكاديمية
New insights into the early mechanisms of epileptogenesis in a zebrafish model of Dravet syndrome.
| العنوان: | New insights into the early mechanisms of epileptogenesis in a zebrafish model of Dravet syndrome. |
|---|---|
| المؤلفون: | Tiraboschi E; Chemical Neuroscience Group, Center for Molecular Medicine Norway, University of Oslo, Oslo, Norway., Martina S; Integrative Cell Signaling Group, Luxembourg Center for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg., van der Ent W; Chemical Neuroscience Group, Center for Molecular Medicine Norway, University of Oslo, Oslo, Norway., Grzyb K; Integrative Cell Signaling Group, Luxembourg Center for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg., Gawel K; Chemical Neuroscience Group, Center for Molecular Medicine Norway, University of Oslo, Oslo, Norway.; Department of Experimental and Clinical Pharmacology, Medical University of Lublin, Lublin, Poland., Cordero-Maldonado ML; Integrative Cell Signaling Group, Luxembourg Center for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg., Poovathingal SK; Integrative Cell Signaling Group, Luxembourg Center for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg., Heintz S; Chemical Neuroscience Group, Center for Molecular Medicine Norway, University of Oslo, Oslo, Norway., Satheesh SV; Molecular Toxicology Group, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway., Brattespe J; Department of Biological Sciences, University of Bergen, Bergen, Norway., Xu J; Department of Biomedicine, University of Bergen, Bergen, Norway., Suster M; allmyhomes, Berlin, Germany., Skupin A; Integrative Cell Signaling Group, Luxembourg Center for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg., Esguerra CV; Chemical Neuroscience Group, Center for Molecular Medicine Norway, University of Oslo, Oslo, Norway.; Department of Pharmacy, University of Oslo, Oslo, Norway. |
| المصدر: | Epilepsia [Epilepsia] 2020 Mar; Vol. 61 (3), pp. 549-560. Date of Electronic Publication: 2020 Feb 24. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Blackwell Science Country of Publication: United States NLM ID: 2983306R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1528-1167 (Electronic) Linking ISSN: 00139580 NLM ISO Abbreviation: Epilepsia Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Malden, MA : Blackwell Science Original Publication: Copenhagen : Munskgaard |
| مواضيع طبية MeSH: | Brain/*physiopathology , Epilepsies, Myoclonic/*genetics , NAV1.1 Voltage-Gated Sodium Channel/*genetics , Neuronal Plasticity/*genetics , Zebrafish Proteins/*genetics, Animals ; Anticonvulsants/pharmacology ; Brain/drug effects ; Brain/metabolism ; Brain/pathology ; CRISPR-Cas Systems ; Cell Proliferation/drug effects ; Diazepam/pharmacology ; Disease Models, Animal ; Electroencephalography ; Epilepsies, Myoclonic/metabolism ; Epilepsies, Myoclonic/pathology ; Epilepsies, Myoclonic/physiopathology ; Fenfluramine/pharmacology ; GABAergic Neurons/drug effects ; GABAergic Neurons/metabolism ; GABAergic Neurons/pathology ; Gene Expression Profiling ; Gliosis/genetics ; Gliosis/pathology ; Locomotion/drug effects ; Mutation, Missense ; NAV1.1 Voltage-Gated Sodium Channel/metabolism ; Neuronal Plasticity/drug effects ; RNA-Seq ; Real-Time Polymerase Chain Reaction ; Serotonin 5-HT2 Receptor Agonists/pharmacology ; Single-Cell Analysis ; Zebrafish ; Zebrafish Proteins/metabolism |
| مستخلص: | 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 5HT 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 (scn1lab mut/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 scn1lab mut/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 scn1lab mut/mut larvae (high-frequency range), with subsequent GABAergic neuronal loss and astrogliosis. Chronic fenfluramine administration completely restored dendritic arbor numbers to normal in scn1lab mut/mut larvae, whereas similar treatment with the benzodiazepine diazepam attenuated seizures, but was ineffective in restoring neuronal cytoarchitecture. BrdU labeling revealed cell overproliferation in scn1lab mut/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 scn1lab mut/mut brain, and present first-time evidence for potential disease modification by fenfluramine. (© 2020 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.) |
| References: | Dravet C. The core Dravet syndrome phenotype. Epilepsia. 2011;52(2):3-9. Claes L, Del-Favero J, Ceulemans B, et al. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet. 2001;68:1327-32. Steel D, Symonds JD, Zuberi SM, Brunklaus A. Dravet syndrome and its mimics: beyond SCN1A. Epilepsia. 2017;58:1807-16. Marini C, Scheffer IE, Nabbout R, et al. The genetics of Dravet syndrome. Epilepsia. 2011;52(2):24-9. Harkin LA, McMahon JM, Iona X, et al. The spectrum of SCN1A-related infantile epileptic encephalopathies. Brain J Neurol. 2007;130:843-52. Ogiwara I, Miyamoto H, Morita N, et al. Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation. J Neurosci. 2007;27:5903-14. Rutecki PA, Grossman RG, Armstrong D, Irish-Loewen S. Electrophysiological connections between the hippocampus and entorhinal cortex in patients with complex partial seizures. J Neurosurg. 1989;70:667-75. Chabardès S, Kahane P, Minotti L, et al. The temporopolar cortex plays a pivotal role in temporal lobe seizures. Brain J Neurol. 2005;128:1818-31. Kelsom C, Lu W. Development and specification of GABAergic cortical interneurons. Cell Biosci. 2013;3:19. Pelkey KA, Chittajallu R, Craig MT, Tricoire L, Wester JC, McBain CJ. Hippocampal GABAergic inhibitory interneurons. Physiol Rev. 2017;97:1619-47. Tsai MS, Lee ML, Chang CY, et al. Functional and structural deficits of the dentate gyrus network coincide with emerging spontaneous seizures in an Scn1a mutant Dravet syndrome model during development. Neurobiol Dis. 2015;77:35-48. Ceulemans B, Boel M, Leyssens K, et al. Successful use of fenfluramine as an add-on treatment for Dravet syndrome. Epilepsia. 2012;53:1131-9. Polster T. Individualized treatment approaches: fenfluramine, a novel antiepileptic medication for the treatment of seizures in Dravet syndrome. Epilepsy Behav. 2019;91:99-102. Martin P, Maurice T, Gammaitoni A, et al. Fenfluramine has in vivo activity as a positive allosteric modulator of sigma-1 receptors. Poster presented at: American Epilepsy Society Annual Meeting; December 1-5, 2017; Washington, DC. Lagae L, Sullivan J, Cross H, et al.ZX008 (fenfluramine) in Dravet syndrome: results of a phase 3, randomized, double-blind, placebo-controlled trial. Poster presented at: American Epilepsy Society Annual Meeting; December 1-5, 2017; Washington, DC. Zhang Y, Kecskés A, Copmans D, et al. Pharmacological characterization of an antisense knockdown zebrafish model of Dravet syndrome: inhibition of epileptic seizures by the serotonin agonist fenfluramine. PLoS One. 2015;10:e0125898. Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med. 1997;337:581-8. Knupp KG, Wirrell EC. Treatment strategies for Dravet syndrome. CNS Drugs. 2018;32:335-50. Baraban SC, Taylor MR, Castro PA, Baier H. Pentylenetetrazole induced changes in zebrafish behavior, neural activity and c-fos expression. Neuroscience. 2005;131:759-68. Afrikanova T, Serruys AS, Buenafe OE, et al. Validation of the zebrafish pentylenetetrazol seizure model: locomotor versus electrographic responses to antiepileptic drugs. PLoS One. 2013;8:e54166. Balciunas D, Wangensteen KJ, Wilber A, et al. Harnessing a high cargo-capacity transposon for genetic applications in vertebrates. PLoS Genet. 2006;2:e169. Zijlmans M, Jiruska P, Zelmann R, Leijten FS, Jefferys JG, Gotman J. High-frequency oscillations as a new biomarker in epilepsy. Ann Neurol. 2012;71:169-78. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25:402-8. Macosko EZ, Basu A, Satija R, et al. Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell. 2015;161(5):1202-14. Ferreira TA, Blackman AV, Oyrer J, et al. Neuronal morphometry directly from bitmap images. Nat Methods. 2014;11:982-4. Ristanović D, Milosević NT, Stulić V. Application of modified Sholl analysis to neuronal dendritic arborization of the cat spinal cord. J Neurosci Methods. 2006;158:212-8. Baraban SC, Dinday MT, Hortopan GA. Drug screening in Scn1a zebrafish mutant identifies clemizole as a potential Dravet syndrome treatment. Nat Commun. 2015;4. Dinday MT, Baraban SC. Large-scale phenotype-based antiepileptic drug screening in a zebrafish model of Dravet syndrome. eNeuro. 2015;2:8-9. McNally JM, McCarley RW. Gamma band oscillations: a key to understanding schizophrenia symptoms and neural circuit abnormalities. Curr Opin Psychiatry. 2016;29:202-10. Mistry AM, Thompson CH, Miller AR, Vanoye CG, George AL Jr, Kearney JA. Strain- and age-dependent hippocampal neuron sodium currents correlate with epilepsy severity in Dravet syndrome mice. Neurobiol Dis. 2014;65:1-11. Hedrich UB, Liautard C, Kirschenbaum D, et al. Impaired action potential initiation in GABAergic interneurons causes hyperexcitable networks in an epileptic mouse model carrying a human Na(V)1.1 mutation. J Neurosci. 2014;34:14874-89. De Lanerolle NC, Kim JH, Robbins RJ, Spencer DD. Hippocampal interneuron loss and plasticity in human temporal lobe epilepsy. Brain Res. 1989;49:387-95. Robbins RJ, Brines ML, Kim JH, et al. A selective loss of somatostatin in the hippocampus of patients with temporal lobe epilepsy. Ann Neurol. 1991;29:325-32. Sundstrom LE, Brana C, Gatherer M, Mepham J, Rougier A. Somatostatin- and neuropeptide Y-synthesizing neurones in the fascia dentata of humans with temporal lobe epilepsy. Brain J Neurol. 2001;124:688-97. Mathern GW, Babb TL, Pretorius JK, Leite JP. Reactive synaptogenesis and neuron densities for neuropeptide Y, somatostatin, and glutamate decarboxylase immunoreactivity in the epileptogenic human fascia dentata. J Neurosci. 1995;15:3990-4004. Swartz BE, Houser CR, Tomiyasu U, et al. Hippocampal cell loss in posttraumatic human epilepsy. Epilepsia. 2006;47:1373-82. Houser CR. Do structural changes in GABA neurons give rise to the epileptic state? Adv Exp Med Biol. 2014;813:151-60. Cobos I, Calcagnotto ME, Vilaythong AJ, et al. Mice lacking Dlx1 show subtype-specific loss of interneurons, reduced inhibition and epilepsy. Nat Neurosci. 2005;8:1059-68. Yu FH, Mantegazza M, Westenbroek RE, et al. Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nat Neurosci. 2006;9:1142-9. Schoonheim PJ, Arrenberg AB, Del Bene F, Baier H. Optogenetic localization and genetic perturbation of saccade-generating neurons in zebrafish. J Neurosci. 2010;30:7111-20. Silenieks LB, Carroll NK, Van Niekerk A, et al. Evaluation of selective 5-HT2C agonists in acute seizure models. ACS Chem Neurosci. 2019;10(7):3284-95. Paizanis E, Kelaï S, Renoir T, Hamon M, Lanfumey L. Life-long hippocampal neurogenesis: environmental, pharmacological and neurochemical modulations. Neurochem Res. 2007;32:1762-71. Daubert EA, Heffron DS, Mandell JW, Condron BG. Serotonergic dystrophy induced by excess serotonin. Mol Cell Neurosci. 2010;44:297-306. Reid CA, Leaw B, Richards KL, et al. Reduced dendritic arborization and hyperexcitability of pyramidal neurons in a Scn1b-based model of Dravet syndrome. Brain. 2014;137:1701-15. Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol. 2010;119:7-35. Hawkins NA, Calhoun JD, Huffman AM, Kearney JA. Gene expression profiling in a mouse model of Dravet syndrome. Exp Neurol. 2019;311:247-56. Favero M, Sotuyo NP, Lopez E, Kearney JA, Goldberg EM. A transient developmental window of fast-spiking interneuron dysfunction in a mouse model of Dravet syndrome. J Neurosci. 2018;38:7912-27. Hawkins NA, Zachwieja NJ, Miller AR, Anderson LL, Kearney JA. Fine mapping of a Dravet syndrome modifier locus on mouse chromosome 5 and candidate gene analysis by RNA-Seq. PLoS Genet. 2016;12(10):e1006398. Kang SK, Hawkins NA, Kearney JA. C57BL/6J and C57BL/6N substrains differentially influence phenotype severity in the Scn1a+/− mouse model of Dravet syndrome. Epilepsia Open. 2019;4:164-9. |
| معلومات مُعتمدة: | International Centre for Molecular Medicine Norway (NCMM) Start up grant; C14/BM/7975668/CaSCAD International National Research Fund of Luxembourg; INTER/DFG/17/11583046 MechEPI (Mechanisms of Epileptogenesis) International National Research Fund of Luxembourg |
| فهرسة مساهمة: | Keywords: Dravet syndrome; epileptogenesis; fenfluramine; sodium channel; zebrafish |
| المشرفين على المادة: | 0 (Anticonvulsants) 0 (NAV1.1 Voltage-Gated Sodium Channel) 0 (Serotonin 5-HT2 Receptor Agonists) 0 (Zebrafish Proteins) 0 (scn1laa protein, zebrafish) 2DS058H2CF (Fenfluramine) Q3JTX2Q7TU (Diazepam) |
| تواريخ الأحداث: | Date Created: 20200226 Date Completed: 20201019 Latest Revision: 20201019 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1111/epi.16456 |
| PMID: | 32096222 |
| قاعدة البيانات: | MEDLINE |
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