Role of Sodium Channels in Epilepsy

Abstract

Voltage-gated sodium channels (VGSCs) are fundamentally important for the generation and coordinated transmission of action potentials throughout the nervous system. It is, therefore, unsurprising that they have been shown to play a central role in the genesis and alleviation of epilepsy. Genetic studies on patients with epilepsy have identified more than 700 mutations among the genes that encode for VGSCs attesting to their role in pathogenesis. Further, many common antiepileptic drugs act on VGSCs to suppress seizure activity. Here, we present an account of the role of VGSCs in epilepsy, both through their pathogenic dysfunction and as targets for pharmacotherapy.

Figure 1.

Scn1a knockout and heterozygous mice show a reduction of sodium currents localized to inhibitory interneurons (Yu et al. 2006). (A) Sample voltage traces from current clamp recordings of mouse γ-aminobutyric acid (GABA)ergic interneurons in the wild-type (WT) (left), heterozygous (middle), and null (right) Scn1a mice, showing a marked reduction in cell excitability in the heterozygous and null mice, summarized in B. (C) The size of action potentials (APs) was also reduced with the mutation, whereas the width of APs increased. (D) Voltage-clamp recordings of isolated sodium currents. (E) I–V curves showing that the mutation does not affect current density in pyramidal neurons (left), whereas it does cause a reduction in current in GABAergic neurons (right) (figure created from data in Yu et al. 2003, 2006).

Figure 2.

The functional consequences of channel mutations can be analyzed on different spatial scales (Wimmer et al. 2010; Egri et al. 2012; Hatch et al. 2014). (A) Current traces from voltage-clamp analysis of Na_V1.2 VGSC α-subunits coexpressed with either the wild-type (WT) β1-subunit (left) or the GEFS⁺ mutation C121W (right) in Chinese hamster ovary (CHO) cells. (B) Voltage dependence of activation for the Na_V1.2, Na_V1.2 + β1 (WT), and Na_V1.2 + β1 (CW) at 22°C and 34°C. Increasing temperature results in a shift of the voltage of half activation, which is most significant in the Na_V1.2 + β1 (CW). (C) Current clamp recordings showing the voltage response of mouse subicular neurons to current injections in WT (left) and C121W heterozygous (right) mice. (D) For most current injections, the C121W mouse showed an increase in action potentials (APs) frequency (E) and the average number of APs per burst. (F) Through tetanic stimulation, network oscillations could be induced in the mouse hippocampus. (G) The latency and (H) interspike interval of these oscillations was reduced in the C121W mouse (figure created from data in Wimmer et al. 2010, Egri et al. 2012, and Hatch et al. 2014). ISI, Interspike interval.