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J Neurophysiol (December 31, 2003). doi:10.1152/jn.00982.2003
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Submitted on October 13, 2003
Accepted on December 29, 2003

Increased Neuronal Firing in Computer Simulations of Sodium Channel Mutations that Cause Generalized Epilepsy with Febrile Seizures Plus

Jay Spampanato1, Ildiko Aradi2, Ivan Soltesz2, and Alan L. Goldin1*

1 Microbiology & Molecular Genetics, University of California, Irvine, Irvine, CA, USA
2 Anatomy & Neurobiology, University of California, Irvine, Irvine, CA, USA

* To whom correspondence should be addressed. E-mail: agoldin{at}uci.edu.

Generalized epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant familial syndrome with a complex seizure phenotype. It is caused by mutations in one of three voltage gated sodium channel subunit genes (SCN1B, SCN1A and SCN2A) and the GABAA receptor {gamma}2 subunit gene (GBRG2). The biophysical characterization of three mutations (T875M, W1204R and R1648H) in SCN1A, the gene encoding the CNS voltage-gated sodium channel {alpha} subunit Nav1.1, demonstrated a variety of functional effects. The T875M mutation enhanced slow inactivation, the W1204R mutation shifted the voltage-dependence of activation and inactivation in the negative direction and the R1648H mutation accelerated recovery from inactivation. To determine how these changes affect neuronal firing, we used the NEURON simulation software to design a computational model based on the experimentally determined properties of each GEFS+ mutant sodium channel and a delayed rectifier potassium channel. The model predicted that W1204R decreased the threshold, T875M increased the threshold, and R1648H did not affect the threshold for firing a single action potential. Despite the different effects on the threshold for firing a single action potential, all of the mutations resulted in an increased propensity to fire repetitive action potentials. In addition, each mutation was capable of driving repetitive firing in a mixed population of mutant and wild-type channels, consistent with the dominant nature of these mutations. These results suggest a common physiological mechanism for epileptogenesis resulting from sodium channel mutations that cause GEFS+.




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