[{"article_type":"original","OA_type":"gold","file":[{"access_level":"open_access","date_created":"2025-12-30T08:35:41Z","file_name":"2025_NeurobioDisease_Currin.pdf","checksum":"abe215be676ed14e9a37fb78b6a5a610","relation":"main_file","date_updated":"2025-12-30T08:35:41Z","file_id":"20896","content_type":"application/pdf","success":1,"file_size":7063352,"creator":"dernst"}],"quality_controlled":"1","volume":212,"OA_place":"publisher","license":"https://creativecommons.org/licenses/by-nc/4.0/","isi":1,"author":[{"id":"e8321fc5-3091-11eb-8a53-83f309a11ac9","last_name":"Currin","orcid":"0000-0002-4809-5059","first_name":"Christopher","full_name":"Currin, Christopher"},{"last_name":"Burman","full_name":"Burman, Richard J.","first_name":"Richard J."},{"full_name":"Fedele, Tommaso","first_name":"Tommaso","last_name":"Fedele"},{"full_name":"Ramantani, Georgia","first_name":"Georgia","last_name":"Ramantani"},{"last_name":"Rosch","full_name":"Rosch, Richard E.","first_name":"Richard E."},{"first_name":"Henning","full_name":"Sprekeler, Henning","last_name":"Sprekeler"},{"first_name":"Joseph V.","full_name":"Raimondo, Joseph V.","last_name":"Raimondo"}],"day":"01","status":"public","year":"2025","intvolume":"       212","type":"journal_article","date_created":"2025-06-08T22:01:22Z","date_published":"2025-08-01T00:00:00Z","oa":1,"fulldoi":"https://doi.org/10.1016/j.nbd.2025.106966","publication_status":"published","tmp":{"image":"/images/cc_by_nc.png","short":"CC BY-NC (4.0)","name":"Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc/4.0/legalcode"},"publication":"Neurobiology of Disease","article_number":"106966","oa_version":"Published Version","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","language":[{"iso":"eng"}],"month":"08","scopus_import":"1","ddc":["570"],"date_updated":"2025-12-30T08:36:36Z","_id":"19794","publisher":"Elsevier","external_id":{"isi":["001501576500001"]},"acknowledgement":"The research leading to these results has received support from the National Research Foundation of South Africa, the Deutscher Akademischer Austauschdienst, NOMIS Foundation, NVIDIA Academic Program, the University of Cape Town, the Anna Mueller Grocholski Foundation, the Swiss National Science Foundation (SNSF: 208184), the Gabriel Foundation, a Wellcome Trust Seed Award (214042/Z/18/Z), the South African Medical Research Council and the FLAIR Fellowship Programme (FLR\\R1\\190829): a partnership between the African Academy of Sciences and the Royal Society funded by the UK Government's Global Challenges Research Fund and a Wellcome Trust International Intermediate Fellowship (222968/Z/21/Z).","title":"Network models incorporating chloride dynamics predict optimal strategies for terminating status epilepticus","article_processing_charge":"Yes","DOAJ_listed":"1","publication_identifier":{"eissn":["1095-953X"],"issn":["0969-9961"]},"abstract":[{"lang":"eng","text":"Status epilepticus (SE), seizures lasting beyond five minutes, is a medical emergency commonly treated with benzodiazepines which enhance GABAA receptor (GABAAR) conductance. Despite widespread use, benzodiazepines fail in over one-third of patients, potentially due to seizure-induced disruption of neuronal chloride (Cl−) homeostasis. Understanding these changes at a network level is crucial for improving clinical translation. Here, we address this using a large-scale spiking neural network model incorporating Cl− dynamics, informed by clinical EEG and experimental slice recordings. Our simulations confirm that the GABAAR reversal potential (EGABA) dictates the pro- or anti-seizure effect of GABAAR conductance modulation, with high EGABA rendering benzodiazepines ineffective or excitatory. We show SE-like activity and EGABA depend non-linearly on Cl− extrusion efficacy and GABAAR conductance. Critically, cell-type specific manipulations reveal that pyramidal cell, not interneuron, Cl− extrusion predominantly determines the severity of SE activity and the response to simulated benzodiazepines. Leveraging these mechanistic insights, we develop a predictive framework mapping network states to Cl− extrusion capacity and GABAergic load, yielding a proposed decision-making strategy to guide therapeutic interventions based on initial treatment response. This work identifies pyramidal cell Cl− handling as a key therapeutic target and demonstrates the utility of biophysically detailed network models for optimising SE treatment protocols."}],"doi":"10.1016/j.nbd.2025.106966","file_date_updated":"2025-12-30T08:35:41Z","citation":{"short":"C. Currin, R.J. Burman, T. Fedele, G. Ramantani, R.E. Rosch, H. Sprekeler, J.V. Raimondo, Neurobiology of Disease 212 (2025).","chicago":"Currin, Christopher, Richard J. Burman, Tommaso Fedele, Georgia Ramantani, Richard E. Rosch, Henning Sprekeler, and Joseph V. Raimondo. “Network Models Incorporating Chloride Dynamics Predict Optimal Strategies for Terminating Status Epilepticus.” <i>Neurobiology of Disease</i>. Elsevier, 2025. <a href=\"https://doi.org/10.1016/j.nbd.2025.106966\">https://doi.org/10.1016/j.nbd.2025.106966</a>.","ama":"Currin C, Burman RJ, Fedele T, et al. Network models incorporating chloride dynamics predict optimal strategies for terminating status epilepticus. <i>Neurobiology of Disease</i>. 2025;212. doi:<a href=\"https://doi.org/10.1016/j.nbd.2025.106966\">10.1016/j.nbd.2025.106966</a>","ieee":"C. Currin <i>et al.</i>, “Network models incorporating chloride dynamics predict optimal strategies for terminating status epilepticus,” <i>Neurobiology of Disease</i>, vol. 212. Elsevier, 2025.","ista":"Currin C, Burman RJ, Fedele T, Ramantani G, Rosch RE, Sprekeler H, Raimondo JV. 2025. Network models incorporating chloride dynamics predict optimal strategies for terminating status epilepticus. Neurobiology of Disease. 212, 106966.","mla":"Currin, Christopher, et al. “Network Models Incorporating Chloride Dynamics Predict Optimal Strategies for Terminating Status Epilepticus.” <i>Neurobiology of Disease</i>, vol. 212, 106966, Elsevier, 2025, doi:<a href=\"https://doi.org/10.1016/j.nbd.2025.106966\">10.1016/j.nbd.2025.106966</a>.","apa":"Currin, C., Burman, R. J., Fedele, T., Ramantani, G., Rosch, R. E., Sprekeler, H., &#38; Raimondo, J. V. (2025). Network models incorporating chloride dynamics predict optimal strategies for terminating status epilepticus. <i>Neurobiology of Disease</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.nbd.2025.106966\">https://doi.org/10.1016/j.nbd.2025.106966</a>"},"corr_author":"1","department":[{"_id":"TiVo"}],"has_accepted_license":"1"},{"title":"Doublecortin mutation leads to persistent defects in the Golgi apparatus and mitochondria in adult hippocampal pyramidal cells","ddc":["570"],"date_updated":"2024-08-06T06:57:39Z","_id":"17067","publisher":"Elsevier","external_id":{"pmid":["35339680"]},"acknowledgement":"We thank Sylvie Dumont for initial aid with laser microdissection and G. Martinez-Lorenzana for experimental help with electron microscopy. We thank the animal experimentation facility and cellular and tissue imaging platforms at the Institut du Fer à Moulin, supported also by the Région Ile de France and the FRC Rotary. The Francis lab was associated with the BioPsy Labex project and the Ecole des Neurosciences de Paris Ile-de-France (ENP) network. Our salaries and lab were supported by Inserm, the Centre national de la recherche scientifique (CNRS) and Sorbonne University. The Francis group obtained the following funding contributing to this project: the European Union (EU- HEALTH-2013, DESIRE, N° 60253), the JTC 2015 Neurodevelopmental Disorders affiliated with the French Agence National de la Recherche (for \r\nNEURON8-Full- 815-006 STEM-MCD, to FF), E-Rare-3, the ERA-Net for Research on Rare Diseases affiliated with the French ANR (ERARE18-049), the European Cooperation on Science and Technology (COST Action CA16118).","department":[{"_id":"SiHi"}],"has_accepted_license":"1","article_processing_charge":"Yes","publication_identifier":{"issn":["0969-9961"]},"abstract":[{"text":"Human doublecortin (DCX) mutations are associated with severe brain malformations leading to aberrant neuron positioning (heterotopia), intellectual disability and epilepsy. DCX is a microtubule-associated protein which plays a key role during neurodevelopment in neuronal migration and differentiation. Dcx knockout (KO) mice show disorganized hippocampal pyramidal neurons. The CA2/CA3 pyramidal cell layer is present as two abnormal layers and disorganized CA3 KO pyramidal neurons are also more excitable than wild-type (WT) cells. To further identify abnormalities, we characterized Dcx KO hippocampal neurons at subcellular, molecular and ultrastructural levels. Severe defects were observed in mitochondria, affecting number and distribution. Also, the Golgi apparatus was visibly abnormal, increased in volume and abnormally organized. Transcriptome analyses from laser microdissected hippocampal tissue at postnatal day 60 (P60) highlighted organelle abnormalities. Ultrastructural studies of CA3 cells performed in P60 (young adult) and > 9 months (mature) tissue showed that organelle defects are persistent throughout life. Locomotor activity and fear memory of young and mature adults were also abnormal: Dcx KO mice consistently performed less well than WT littermates, with defects becoming more severe with age. Thus, we show that disruption of a neurodevelopmentally-regulated gene can lead to permanent organelle anomalies contributing to abnormal adult behavior.","lang":"eng"}],"citation":{"chicago":"Stouffer, Melissa A, R. Khalaf-Nazzal, C. Cifuentes-Diaz, G. Albertini, E. Bandet, G. Grannec, V. Lavilla, et al. “Doublecortin Mutation Leads to Persistent Defects in the Golgi Apparatus and Mitochondria in Adult Hippocampal Pyramidal Cells.” <i>Neurobiology of Disease</i>. Elsevier, 2022. <a href=\"https://doi.org/10.1016/j.nbd.2022.105702\">https://doi.org/10.1016/j.nbd.2022.105702</a>.","short":"M.A. Stouffer, R. Khalaf-Nazzal, C. Cifuentes-Diaz, G. Albertini, E. Bandet, G. Grannec, V. Lavilla, J.-F. Deleuze, R. Olaso, M. Nosten-Bertrand, F. Francis, Neurobiology of Disease 168 (2022).","ama":"Stouffer MA, Khalaf-Nazzal R, Cifuentes-Diaz C, et al. Doublecortin mutation leads to persistent defects in the Golgi apparatus and mitochondria in adult hippocampal pyramidal cells. <i>Neurobiology of Disease</i>. 2022;168. doi:<a href=\"https://doi.org/10.1016/j.nbd.2022.105702\">10.1016/j.nbd.2022.105702</a>","ieee":"M. A. Stouffer <i>et al.</i>, “Doublecortin mutation leads to persistent defects in the Golgi apparatus and mitochondria in adult hippocampal pyramidal cells,” <i>Neurobiology of Disease</i>, vol. 168. Elsevier, 2022.","ista":"Stouffer MA, Khalaf-Nazzal R, Cifuentes-Diaz C, Albertini G, Bandet E, Grannec G, Lavilla V, Deleuze J-F, Olaso R, Nosten-Bertrand M, Francis F. 2022. Doublecortin mutation leads to persistent defects in the Golgi apparatus and mitochondria in adult hippocampal pyramidal cells. Neurobiology of Disease. 168, 105702.","mla":"Stouffer, Melissa A., et al. “Doublecortin Mutation Leads to Persistent Defects in the Golgi Apparatus and Mitochondria in Adult Hippocampal Pyramidal Cells.” <i>Neurobiology of Disease</i>, vol. 168, 105702, Elsevier, 2022, doi:<a href=\"https://doi.org/10.1016/j.nbd.2022.105702\">10.1016/j.nbd.2022.105702</a>.","apa":"Stouffer, M. A., Khalaf-Nazzal, R., Cifuentes-Diaz, C., Albertini, G., Bandet, E., Grannec, G., … Francis, F. (2022). Doublecortin mutation leads to persistent defects in the Golgi apparatus and mitochondria in adult hippocampal pyramidal cells. <i>Neurobiology of Disease</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.nbd.2022.105702\">https://doi.org/10.1016/j.nbd.2022.105702</a>"},"file_date_updated":"2024-08-06T06:54:24Z","doi":"10.1016/j.nbd.2022.105702","article_number":"105702","month":"06","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","language":[{"iso":"eng"}],"scopus_import":"1","oa_version":"Published Version","date_created":"2024-05-29T06:10:05Z","date_published":"2022-06-15T00:00:00Z","oa":1,"status":"public","year":"2022","intvolume":"       168","type":"journal_article","fulldoi":"https://doi.org/10.1016/j.nbd.2022.105702","publication_status":"published","tmp":{"image":"/images/cc_by_nc_nd.png","short":"CC BY-NC-ND (4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)"},"publication":"Neurobiology of Disease","volume":168,"pmid":1,"article_type":"original","file":[{"relation":"main_file","date_updated":"2024-08-06T06:54:24Z","checksum":"b705d3d23d0b424ba29920be7ab64c23","file_name":"2022_NeurobioDisease_Stouffer.pdf","date_created":"2024-08-06T06:54:24Z","access_level":"open_access","creator":"dernst","file_size":8890818,"success":1,"file_id":"17398","content_type":"application/pdf"}],"quality_controlled":"1","author":[{"full_name":"Stouffer, Melissa A","first_name":"Melissa A","id":"4C9372C4-F248-11E8-B48F-1D18A9856A87","last_name":"Stouffer"},{"first_name":"R.","full_name":"Khalaf-Nazzal, R.","last_name":"Khalaf-Nazzal"},{"full_name":"Cifuentes-Diaz, C.","first_name":"C.","last_name":"Cifuentes-Diaz"},{"first_name":"G.","full_name":"Albertini, G.","last_name":"Albertini"},{"last_name":"Bandet","full_name":"Bandet, E.","first_name":"E."},{"first_name":"G.","full_name":"Grannec, G.","last_name":"Grannec"},{"last_name":"Lavilla","first_name":"V.","full_name":"Lavilla, V."},{"full_name":"Deleuze, J.-F.","first_name":"J.-F.","last_name":"Deleuze"},{"first_name":"R.","full_name":"Olaso, R.","last_name":"Olaso"},{"last_name":"Nosten-Bertrand","full_name":"Nosten-Bertrand, M.","first_name":"M."},{"full_name":"Francis, F.","first_name":"F.","last_name":"Francis"}],"day":"15","license":"https://creativecommons.org/licenses/by-nc-nd/4.0/"}]