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In this study, we modeled AP2M1-DEE in Drosophila melanogaster to gain deeper insights into the underlying disease mechanisms. Pan-neuronal RNA interference against the Drosophila AP2M1 ortholog, AP-2\u00b5, resulted in a consistent heat-sensitive paralysis phenotype and altered morphology in class IV dendritic arborization neurons. Unexpectedly, affected flies were resistant to antiseizure medications and exhibited decreased susceptibility to electrically induced seizures. A CRISPR-engineered fly line carrying the recurrent human disease variant p.Arg170Trp displayed a milder, seizure-resistant phenotype. Although these findings contrast with the human phenotype, they align with previous studies on other clathrin-mediated endocytosis-related genes in Drosophila. Our results suggest that hyperexcitability and seizures in AP2M1-DEE may stem from broader defects in neuronal development rather than direct synaptic dysfunction.<\/jats:p>","DOI":"10.1242\/dmm.052419","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T09:25:04Z","timestamp":1759137904000},"source":"Crossref","is-referenced-by-count":3,"title":["Modeling AP2M1 developmental and epileptic encephalopathy in\n                    <i>Drosophila<\/i>"],"prefix":"10.1242","volume":"18","author":[{"given":"Robin A.","family":"Karge","sequence":"first","affiliation":[{"name":"RWTH Aachen University 1 Section of Epileptology, Department of Neurology , , 52074 Aachen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4236-8403","authenticated-orcid":false,"given":"Florian P.","family":"Fischer","sequence":"additional","affiliation":[{"name":"RWTH Aachen University 1 Section of Epileptology, Department of Neurology , , 52074 Aachen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Sch\u00fcth","sequence":"additional","affiliation":[{"name":"RWTH Aachen University 1 Section of Epileptology, Department of Neurology , , 52074 Aachen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aileen","family":"Wechner","sequence":"additional","affiliation":[{"name":"RWTH Aachen University 1 Section of Epileptology, Department of Neurology , , 52074 Aachen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Peter","sequence":"additional","affiliation":[{"name":"RWTH Aachen University 1 Section of Epileptology, Department of Neurology , , 52074 Aachen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2787-044X","authenticated-orcid":false,"given":"Lukas A.","family":"Kilo","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology, Institute for Neurobiology and Biomedical Life Science, RWTH Aachen University 2 , 52074 Aachen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mato","family":"Dichter","sequence":"additional","affiliation":[{"name":"RWTH Aachen University 3 Department of Neurology , , 52074 Aachen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0428-7462","authenticated-orcid":false,"given":"Aaron","family":"Voigt","sequence":"additional","affiliation":[{"name":"RWTH Aachen University 3 Department of Neurology , , 52074 Aachen ,","place":["Germany"]},{"name":"JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum J\u00fclich GmbH and RWTH Aachen University 4 , 52074 Aachen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8679-5515","authenticated-orcid":false,"given":"Gaia","family":"Tavosanis","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology, Institute for Neurobiology and Biomedical Life Science, RWTH Aachen University 2 , 52074 Aachen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3074-5612","authenticated-orcid":false,"given":"Karen M. J.","family":"van Loo","sequence":"additional","affiliation":[{"name":"RWTH Aachen University 1 Section of Epileptology, Department of Neurology , , 52074 Aachen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6883-3071","authenticated-orcid":false,"given":"Henner","family":"Koch","sequence":"additional","affiliation":[{"name":"RWTH Aachen University 1 Section of Epileptology, Department of Neurology , , 52074 Aachen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0806-5592","authenticated-orcid":false,"given":"Yvonne G.","family":"Weber","sequence":"additional","affiliation":[{"name":"RWTH Aachen University 1 Section of Epileptology, Department of Neurology , , 52074 Aachen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1460-6623","authenticated-orcid":false,"given":"Stefan","family":"Wolking","sequence":"additional","affiliation":[{"name":"RWTH Aachen University 1 Section of Epileptology, Department of Neurology , , 52074 Aachen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2025,11,21]]},"reference":[{"key":"2025112104464516700_DMM052419C1","doi-asserted-by":"publisher","first-page":"pdb.prot5453","DOI":"10.1101\/pdb.prot5453","article-title":"Electrophysiological recordings from the Drosophila giant fiber system (GFS)","volume":"2010","author":"Allen","year":"2010","journal-title":"Cold Spring Harb. 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