{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T22:01:40Z","timestamp":1792879300986,"version":"4.5.0"},"reference-count":49,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2020,2,24]],"date-time":"2020-02-24T00:00:00Z","timestamp":1582502400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Centre for Molecular Medicine Norway (NCMM) Start up grant"},{"name":"National Research Fund of Luxembourg","award":["C14\/BM\/7975668\/CaSCAD"],"award-info":[{"award-number":["C14\/BM\/7975668\/CaSCAD"]}]},{"name":"National Research Fund of Luxembourg","award":["INTER\/DFG\/17\/11583046 MechEPI (Mechanisms of Epileptogenesis)"],"award-info":[{"award-number":["INTER\/DFG\/17\/11583046 MechEPI (Mechanisms of Epileptogenesis)"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2020,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      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\u2010modifying activity of the 5HT\n                      <jats:sub>2<\/jats:sub>\n                      receptor agonist fenfluramine.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We used CRISPR\/Cas9 mutagenesis to introduce a missense mutation, designed to perturb ion transport function in all channel isoforms, into\n                      <jats:italic>scn1lab<\/jats:italic>\n                      , the zebrafish orthologue of\n                      <jats:italic>SCN1A<\/jats:italic>\n                      (encoding voltage\u2010gated sodium channel alpha subunit 1). We performed behavioral analysis and electroencephalographic recordings to measure convulsions and epileptiform discharges, followed by single\u2010cell RNA\u2010Seq, morphometric analysis of transgenic reporter\u2010labeled \u03b3\u2010aminobutyric acidergic (GABAergic) neurons, and pharmacological profiling of mutant larvae.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Homozygous mutant (\n                      <jats:italic>\n                        scn1lab\n                        <jats:sup>mut\/mut<\/jats:sup>\n                      <\/jats:italic>\n                      ) larvae displayed spontaneous seizures with interictal, preictal, and ictal discharges (mean\u00a0=\u00a07.5 per 20\u2010minute recording;\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a0.0001; one\u2010way analysis of variance). Drop\u2010Seq analysis revealed a 2:1 shift in the ratio of glutamatergic to GABAergic neurons in\n                      <jats:italic>\n                        scn1lab\n                        <jats:sup>mut\/mut<\/jats:sup>\n                      <\/jats:italic>\n                      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 (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a0.001; n\u00a0=\u00a015 mutant, n\u00a0=\u00a016 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\n                      <jats:italic>\n                        scn1lab\n                        <jats:sup>mut\/mut<\/jats:sup>\n                      <\/jats:italic>\n                      larvae (high\u2010frequency range), with subsequent GABAergic neuronal loss and astrogliosis. Chronic fenfluramine administration completely restored dendritic arbor numbers to normal in\n                      <jats:italic>\n                        scn1lab\n                        <jats:sup>mut\/mut<\/jats:sup>\n                      <\/jats:italic>\n                      larvae, whereas similar treatment with the benzodiazepine diazepam attenuated seizures, but was ineffective in restoring neuronal cytoarchitecture. BrdU labeling revealed cell overproliferation in\n                      <jats:italic>\n                        scn1lab\n                        <jats:sup>mut\/mut<\/jats:sup>\n                      <\/jats:italic>\n                      larval brains that were rescued by fenfluramine but not diazepam.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>\n                      Our findings provide novel insights into early mechanisms of DS pathogenesis, describe dynamic cell population changes in the\n                      <jats:italic>\n                        scn1lab\n                        <jats:sup>mut\/mut<\/jats:sup>\n                      <\/jats:italic>\n                      brain, and present first\u2010time evidence for potential disease modification by fenfluramine.\n                    <\/jats:p>\n                  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