HOW DO MUTATIONS IN VOLTAGE-GATED SODIUM CHANNELS CAUSE EPILEPSY?

Objective: To understand how naturally-occurring mutations in voltage-gated sodium channels alter neuronal electrophysiology to cause inherited epilepsy syndromes.

Methods: We examined two different mutations responsible for generalized epilepsy with febrile seizures plus (GEFS+), one (D188V-α1.1) in the pore-forming α subunit of the sodium channel and the other (C121W-β1) in the auxiliary β1 subunit. To investigate how these mutations affect channel function, we introduced them into cloned sodium channel subunits, using standard site-directed mutagenesis procedures, expressed the mutant channels in Chinese hamster ovary cells and examined the functional properties of the expressed channels by whole cell voltage clamp recording.

Results: Whole cell voltage-activated sodium currents in cells expressing D188V-α1.1 mutant channels were indistinguishable from currents in cells expressing wild type channels in terms of current amplitude, current time course, levels of persistent current, and the voltage-dependence of activation and steady state inactivation. However, mutant currents showed less attenuation of amplitude than wild type currents during periods of high frequency activation. Mutation C121W-β1 caused a similar affect on frequency-dependent attenuation, suggesting that this is a common characteristic of mutant sodium channels responsible for epilepsy.

Conclusion: Frequency-dependent attenuation of sodium currents serves as a brake on neuronal excitability during periods of intense activity, and thus may act to suppress the initiation and/or spread of seizures. Since mutant channels are more resistant to attenuation during episodes of high frequency activity, they may be more capable of sustaining seizure activity.

Keywords: Channelopathy, GEFS+, Voltage-gated sodium channel, patch clamp