期刊
NATURE MEDICINE
卷 21, 期 12, 页码 1436-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3987
关键词
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资金
- German Federal Ministry of Education and Research (NGFNplus/EMINet project) [01GS0831, 01GQ0809]
- Deutsche Forschungsgemeinschaft (DFG) [IS63/3-1/2, IS63/4-1, SFB936, B3, SPP1665 IS63/5-1, Ha4466/3-1]
- Human Frontier Science Program
- Werner-Otto-Stiftung (Hamburg, Germany)
- Hamburg macht Kinder gesund e.V. (Hamburg, Germany)
- L'Agence Nationale de la Recherche (ANR) [ANR-13-NEUC-005-01]
- INSERM
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.
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