Journal article

Axon initial segment dysfunction in a mouse model of genetic epilepsy with febrile seizures plus

Verena C Wimmer, Christopher A Reid, Suzanne Mitchell, Kay L Richards, Byron B Scaf, Bryan T Leaw, Elisa L Hill, Michel Royeck, Marie-Therese Horstmann, Brett A Cromer, Philip J Davies, Ruwei Xu, Holger Lerche, Samuel F Berkovic, Heinz Beck, Steven Petrou

JOURNAL OF CLINICAL INVESTIGATION | AMER SOC CLINICAL INVESTIGATION INC | Published : 2010

Abstract

Febrile seizures are a common childhood seizure disorder and a defining feature of genetic epilepsy with febrile seizures plus (GEFS+), a syndrome frequently associated with Na+ channel mutations. Here, we describe the creation of a knockin mouse heterozygous for the C121W mutation of the beta1 Na+ channel accessory subunit seen in patients with GEFS+. Heterozygous mice with increased core temperature displayed behavioral arrest and were more susceptible to thermal challenge than wild-type mice. Wild-type beta1 was most concentrated in the membrane of axon initial segments (AIS) of pyramidal neurons, while the beta1(C121W) mutant subunit was excluded from AIS membranes. In addition, AIS func..

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Grants

Awarded by NHMRC


Awarded by European Union


Awarded by BMBF/NGFNplus


Awarded by Deutsche Forschungsgemeinschaft


Funding Acknowledgements

The authors would like to thank Elena Gazina and Nathan Myhill. This work was supported by NHMRC program grant 400121 (to S. Petrou and S.F. Berkovic), by the European Union (contract number LSH-CT-2006-037315, EPICURE, FP6) and BMBF/NGFNplus (01GS08122 to H. Beck; 01GS08123 to H. Lerche), the Deutsche Forschungsgemeinschaft (SFB-TR3 to H. Beck; Le1030/8-2, /10-1 to H. Lerche), the German Science Foundation (to M.T. Horstmann), funding from Bionomics Ltd. (to S. Petrou), and an Australian Research Council Future Fellowship (to C. Reid).