Marguet, Stephan Lawrence, Le-Schulte, Vu Thao Quyen, Merseburg, Andrea, Neu, Axel ORCID: 0000-0001-7045-7194, Eichler, Ronny, Jakovcevski, Igor ORCID: 0000-0001-7673-9600, Ivanov, Anton ORCID: 0000-0002-8650-6322, Hanganu-Opatz, Ileana Livia, Bernard, Christophe, Morellini, Fabio and Isbrandt, Dirk (2015). Treatment during a vulnerable developmental period rescues a genetic epilepsy. Nat. Med., 21 (12). S. 1436 - 1448. NEW YORK: NATURE PUBLISHING GROUP. ISSN 1546-170X

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Marguet, Stephan LawrenceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Le-Schulte, Vu Thao QuyenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merseburg, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neu, AxelUNSPECIFIEDorcid.org/0000-0001-7045-7194UNSPECIFIED
Eichler, RonnyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jakovcevski, IgorUNSPECIFIEDorcid.org/0000-0001-7673-9600UNSPECIFIED
Ivanov, AntonUNSPECIFIEDorcid.org/0000-0002-8650-6322UNSPECIFIED
Hanganu-Opatz, Ileana LiviaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bernard, ChristopheUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morellini, FabioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Isbrandt, DirkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-385424
DOI: 10.1038/nm.3987
Journal or Publication Title: Nat. Med.
Volume: 21
Number: 12
Page Range: S. 1436 - 1448
Date: 2015
Publisher: NATURE PUBLISHING GROUP
Place of Publication: NEW YORK
ISSN: 1546-170X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CATION-CHLORIDE COTRANSPORTERS; POTASSIUM CHANNEL GENE; NEONATAL SEIZURE MODEL; VISUAL-CORTEX; MOUSE-BRAIN; SYNAPTIC PLASTICITY; INHERITED EPILEPSY; SPINDLE BURSTS; IN-VIVO; BUMETANIDEMultiple languages
Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/38542

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