title: Treatment during a vulnerable developmental period rescues a genetic epilepsy.
abstract: The nervous system is vulnerable to perturbations during specific developmental periods. Insults during such susceptible time windows can have long-term consequences, including the development of neurological diseases such as epilepsy. Here we report that a pharmacological intervention timed during a vulnerable neonatal period of cortical development prevents pathology in a genetic epilepsy model. By using mice with dysfunctional Kv7 voltage-gated K(+) channels, which are mutated in human neonatal epilepsy syndromes, we demonstrate the safety and efficacy of the sodium-potassium-chloride cotransporter NKCC1 antagonist bumetanide, which was administered during the first two postnatal weeks. In Kv7 current-deficient mice, which normally display epilepsy, hyperactivity and stereotypies as adults, transient bumetanide treatment normalized neonatal in vivo cortical network and hippocampal neuronal activity, prevented structural damage in the hippocampus and restored wild-type adult behavioral phenotypes. Furthermore, bumetanide treatment did not adversely affect control mice. These results suggest that in individuals with disease susceptibility, timing prophylactically safe interventions to specific windows during development may prevent or arrest disease progression.
authors.affiliation: Experimental Neurophysiology, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.|Institute for Molecular and Behavioral Neuroscience, University of Cologne, Cologne, Germany.|Experimental Neuropediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Stephan Lawrence
authors.initials: SL
authors.lastname: Marguet
authors.affiliation: Experimental Neuropediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Vu Thao Quyen
authors.initials: VT
authors.lastname: Le-Schulte
authors.affiliation: Experimental Neurophysiology, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.|Institute for Molecular and Behavioral Neuroscience, University of Cologne, Cologne, Germany.|Experimental Neuropediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Merseburg
authors.affiliation: Experimental Neuropediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Neu
authors.affiliation: Experimental Neuropediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ronny
authors.initials: R
authors.lastname: Eichler
authors.affiliation: Experimental Neurophysiology, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.|Institute for Molecular and Behavioral Neuroscience, University of Cologne, Cologne, Germany.
authors.forename: Igor
authors.initials: I
authors.lastname: Jakovcevski
authors.affiliation: Aix Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Neurosciences des Systèmes (INS), Unité Mixte de Recherche (UMR) S1106, Marseille, France.
authors.forename: Anton
authors.initials: A
authors.lastname: Ivanov
authors.affiliation: Developmental Neurophysiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ileana Livia
authors.initials: IL
authors.lastname: Hanganu-Opatz
authors.affiliation: Aix Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Neurosciences des Systèmes (INS), Unité Mixte de Recherche (UMR) S1106, Marseille, France.
authors.forename: Christophe
authors.identifier: http://orcid.org/0000-0003-3014-1966
authors.initials: C
authors.lastname: Bernard
authors.affiliation: Experimental Neuropediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Behavioral Biology Unit, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Fabio
authors.initials: F
authors.lastname: Morellini
authors.affiliation: Experimental Neurophysiology, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.|Institute for Molecular and Behavioral Neuroscience, University of Cologne, Cologne, Germany.|Experimental Neuropediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Dirk
authors.identifier: http://orcid.org/0000-0002-4720-1016
authors.initials: D
authors.lastname: Isbrandt
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002034:Bumetanide / Q000494:pharmacology / Q000627:therapeutic use; D056547:CA1 Region, Hippocampal / Q000473:pathology; D003071:Cognition / Q000187:drug effects; D004569:Electroencephalography; D004622:Embryo, Mammalian / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D005260:Female; D048788:Growth and Development / Q000187:drug effects; D007249:Inflammation / Q000473:pathology; D051656:KCNQ Potassium Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D009415:Nerve Net / Q000187:drug effects / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D064506:Solute Carrier Family 12, Member 2 / Q000378:metabolism; D013997:Time Factors
chemical_list: D051656:KCNQ Potassium Channels; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D064506:Solute Carrier Family 12, Member 2; D002034:Bumetanide