دورية أكاديمية
Modeling mTORopathy-related epilepsy in cultured murine hippocampal neurons using the multi-electrode array.
| العنوان: | Modeling mTORopathy-related epilepsy in cultured murine hippocampal neurons using the multi-electrode array. |
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| المؤلفون: | Heuvelmans AM; Department of Clinical Genetics, Erasmus Medical Center, Rotterdam 3015 CN, the Netherlands; The ENCORE Expertise Center for Neurodevelopmental Disorders, Rotterdam 3015 CN, the Netherlands. Electronic address: a.heuvelmans@erasmusmc.nl., Proietti Onori M; The ENCORE Expertise Center for Neurodevelopmental Disorders, Rotterdam 3015 CN, the Netherlands; Department of Neuroscience, Erasmus Medical Center, Rotterdam 3015 CN, the Netherlands., Frega M; Department of Clinical Neurophysiology, University of Twente, 7522 NB Enschede, the Netherlands., de Hoogen JD; Department of Neuroscience, Erasmus Medical Center, Rotterdam 3015 CN, the Netherlands., Nel E; Department of Clinical Genetics, Erasmus Medical Center, Rotterdam 3015 CN, the Netherlands., Elgersma Y; Department of Clinical Genetics, Erasmus Medical Center, Rotterdam 3015 CN, the Netherlands; The ENCORE Expertise Center for Neurodevelopmental Disorders, Rotterdam 3015 CN, the Netherlands., van Woerden GM; Department of Clinical Genetics, Erasmus Medical Center, Rotterdam 3015 CN, the Netherlands; The ENCORE Expertise Center for Neurodevelopmental Disorders, Rotterdam 3015 CN, the Netherlands; Department of Neuroscience, Erasmus Medical Center, Rotterdam 3015 CN, the Netherlands. Electronic address: g.vanwoerden@erasmusmc.nl. |
| المصدر: | Experimental neurology [Exp Neurol] 2024 Sep; Vol. 379, pp. 114874. Date of Electronic Publication: 2024 Jun 22. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Academic Press Country of Publication: United States NLM ID: 0370712 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2430 (Electronic) Linking ISSN: 00144886 NLM ISO Abbreviation: Exp Neurol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Orlando Fl : Academic Press Original Publication: New York. |
| مواضيع طبية MeSH: | Hippocampus* , Neurons*/drug effects , Neurons*/metabolism , Epilepsy*/pathology , Tuberous Sclerosis Complex 1 Protein*/genetics, Animals ; Mice ; Cells, Cultured ; TOR Serine-Threonine Kinases/metabolism ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Disease Models, Animal ; Ras Homolog Enriched in Brain Protein/genetics ; Mice, Knockout ; Mice, Inbred C57BL |
| مستخلص: | The mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway is a ubiquitous cellular pathway. mTORopathies, a group of disorders characterized by hyperactivity of the mTORC1 pathway, illustrate the prominent role of the mTOR pathway in disease pathology, often profoundly affecting the central nervous system. One of the most debilitating symptoms of mTORopathies is drug-resistant epilepsy, emphasizing the urgent need for a deeper understanding of disease mechanisms to develop novel anti-epileptic drugs. In this study, we explored the multiwell Multi-electrode array (MEA) system as a tool to identify robust network activity parameters in an approach to model mTORopathy-related epilepsy in vitro. To this extent, we cultured mouse primary hippocampal neurons on the multiwell MEA to identify robust network activity phenotypes in mTORC1-hyperactive neuronal networks. mTOR-hyperactivity was induced either through deletion of Tsc1 or overexpression of a constitutively active RHEB variant identified in patients, RHEBp.P37L. mTORC1 dependency of the phenotypes was assessed using rapamycin, and vigabatrin was applied to treat epilepsy-like phenotypes. We show that hyperactivity of the mTORC1 pathway leads to aberrant network activity. In both the Tsc1-KO and RHEB-p.P37L models, we identified changes in network synchronicity, rhythmicity, and burst characteristics. The presence of these phenotypes is prevented upon early treatment with the mTORC1-inhibitor rapamycin. Application of rapamycin in mature neuronal cultures could only partially rescue the network activity phenotypes. Additionally, treatment with the anti-epileptic drug vigabatrin reduced network activity and restored burst characteristics. Taken together, we showed that mTORC1-hyperactive neuronal cultures on the multiwell MEA system present reliable network activity phenotypes that can be used as an assay to explore the potency of new drug treatments targeting epilepsy in mTORopathy patients and may give more insights into the pathophysiological mechanisms underlying epilepsy in these patients. Competing Interests: Declaration of competing interest Geeske van Woerden reports financial support was provided by Dutch Research Council. Geeske van Woerden reports financial support was provided by Dutch TSC foundation (STSN). Ype Elgersma reports financial support was provided by Epilepsie fonds. Martina Proietti Onori reports a relationship with Ionis Pharmaceuticals Inc. that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Epilepsy; Multi-electrode array; Network activity; Primary hippocampal neurons; Rapamycin; Vigabatrin; mTORopathy |
| المشرفين على المادة: | 0 (Tuberous Sclerosis Complex 1 Protein) EC 2.7.11.1 (TOR Serine-Threonine Kinases) EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) 0 (Tsc1 protein, mouse) 0 (Ras Homolog Enriched in Brain Protein) 0 (Rheb protein, mouse) |
| تواريخ الأحداث: | Date Created: 20240624 Date Completed: 20240728 Latest Revision: 20240728 |
| رمز التحديث: | 20240729 |
| DOI: | 10.1016/j.expneurol.2024.114874 |
| PMID: | 38914275 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1090-2430 |
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| DOI: | 10.1016/j.expneurol.2024.114874 |