Developmental impact of a familial GABAA receptor epilepsy mutation

被引:47
作者
Chiu, Cindy [1 ]
Reid, Christopher A. [1 ]
Tan, Heneu O. [1 ]
Davies, Philip J. [1 ]
Single, Frank N. [2 ]
Koukoulas, Irene [1 ]
Berkovic, Samuel F. [3 ]
Tan, Seong-Seng [1 ]
Sprengel, Rolf [2 ]
Jones, Mathew V. [4 ]
Petrou, Steven [1 ]
机构
[1] Univ Melbourne, Howard Florey Inst, Parkville, Vic 3010, Australia
[2] Max Planck Inst Med Res, Heidelberg, Germany
[3] Univ Melbourne, Dept Med, Melbourne, Vic, Australia
[4] Univ Wisconsin, Dept Physiol, Madison, WI 53706 USA
基金
英国医学研究理事会;
关键词
D O I
10.1002/ana.21440
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Objective: A major goal of epilepsy research is to understand the molecular and functional basis of seizure genesis. A human GABA(A) gamma 2 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. GABAA 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.
引用
收藏
页码:284 / 293
页数:10
相关论文
共 35 条
[21]  
Novak A, 2000, GENESIS, V28, P147, DOI 10.1002/1526-968X(200011/12)28:3/4<147::AID-GENE90>3.0.CO
[22]  
2-G
[23]   Is there more to GABA than synaptic inhibition? [J].
Owens, DF ;
Kriegstein, AR .
NATURE REVIEWS NEUROSCIENCE, 2002, 3 (09) :715-727
[24]   Genetic disruption of cortical interneuron development causes region- and GABA cell type-specific deficits, epilepsy, and behavioral dysfunction [J].
Powell, EM ;
Campbell, DB ;
Stanwood, GD ;
Davis, C ;
Noebels, JL ;
Levitt, P .
JOURNAL OF NEUROSCIENCE, 2003, 23 (02) :622-631
[25]   New strategies for the identification of drugs to prevent the development or progression of epilepsy [J].
Schmidt, D ;
Rogawski, MA .
EPILEPSY RESEARCH, 2002, 50 (1-2) :71-78
[26]   Stringent doxycycline dependent control of CRE recombinase in vivo -: art. no. e134 [J].
Schönig, K ;
Schwenk, F ;
Rajewsky, K ;
Bujard, H .
NUCLEIC ACIDS RESEARCH, 2002, 30 (23) :e134
[27]   The γ2 subunit of GABAA receptors is required for maintenance of receptors at mature synapses [J].
Schweizer, C ;
Balsiger, S ;
Bluethmann, H ;
Mansuy, IM ;
Fritschy, JM ;
Mohler, H ;
Lüscher, B .
MOLECULAR AND CELLULAR NEUROSCIENCE, 2003, 24 (02) :442-450
[28]   A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells [J].
Schwenk, F ;
Baron, U ;
Rajewsky, K .
NUCLEIC ACIDS RESEARCH, 1995, 23 (24) :5080-5081
[29]   Reduced cortical inhibition in a mouse model of familial childhood absence epilepsy [J].
Tan, Heneu O. ;
Reid, Christopher A. ;
Single, Frank N. ;
Davies, Philip J. ;
Chiu, Cindy ;
Murphy, Susan ;
Clarke, Alison L. ;
Dibbens, Leanne ;
Krestel, Heinz ;
Mulley, John C. ;
Jones, Mathew V. ;
Seeburg, Peter H. ;
Sakmann, Bert ;
Berkovic, Samuel F. ;
Sprengel, Rolf ;
Petrou, Steven .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (44) :17536-17541
[30]   Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: Meta-analysis of controlled trials [J].
Temkin, NR .
EPILEPSIA, 2001, 42 (04) :515-524