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  Developmental impact of a familial GABAA receptor epilepsy mutation

Chiu, C., Reid, C. A., Heneu, O. T., Davies, P. J., Single, F. N., Koukoulas, I., et al. (2008). Developmental impact of a familial GABAA receptor epilepsy mutation. Annals of Neurology, 64(3), 284-293. doi:10.1002/ana.21440.

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 Creators:
Chiu, Cindy, Author
Reid, Christopher A., Author
Heneu, O. Tan, Author
Davies, Philip J., Author
Single, Frank Nicolai1, Author              
Koukoulas, Irene, Author
Berkovic, Samuel F., Author
Tan, Seong-Seng, Author
Sprengel, Rolf1, Author              
Jones, Mathew V., Author
Petrou, Steven2, Author              
Affiliations:
1Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497704              
2Department of Cell Physiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497701              

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 Abstract: OBJECTIVE: A major goal of epilepsy research is to understand the molecular and functional basis of seizure genesis. A human GABA(A) gamma2 gene mutation (R43Q) is associated with generalized epilepsy. Introduction of this mutation into a mouse by gene targeting recapitulates the human phenotype demonstrating a strong genotype to phenotype link. GABA(A) receptors play a role in the moment-to-moment control of brain function and also on the long-term wiring of the brain by directing neuronal development. Our objective was to determine whether developmental expression of the mutation alters seizure susceptibility later in life. METHODS: A tetracycline-based conditional model for activation of a hypomorphic Q43 disease allele was created and validated. Seizure susceptibility was assessed using the subcutaneous pentylenetetrazole model. RESULTS: Seizure susceptibility was significantly reduced in mice where the Q43 allele was suppressed during development. INTERPRETATION: These results demonstrate that a human epilepsy-causing mutation impacts network stability during a critical developmental period. These data suggest that identification of presymptomatic children may provide a window for therapeutic intervention before overt symptoms are observed, potentially altering the course of epileptogenesis.

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Language(s): eng - English
 Dates: 2007-12-092008-05-162008-09-28
 Publication Status: Published in print
 Pages: 10
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
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Title: Annals of Neurology
Source Genre: Journal
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Publ. Info: Boston : American Neurological Association
Pages: - Volume / Issue: 64 (3) Sequence Number: - Start / End Page: 284 - 293 Identifier: ISSN: 0364-5134
CoNE: https://pure.mpg.de/cone/journals/resource/954925523748