Model systems for studying cellular mechanisms of SCN1A-related epilepsy

Abstract

Mutations in SCN1A, the gene encoding voltage-gated sodium channel NaV1.1, cause a spectrum of epilepsy disorders that range from genetic epilepsy with febrile seizures plus to catastrophic disorders such as Dravet syndrome. To date, more than 1,250 mutations in SCN1A have been linked to epilepsy. Distinct effects of individual SCN1A mutations on neuronal function are likely to contribute to variation in disease severity and response to treatment in patients. Several model systems have been used to explore seizure genesis in SCN1A epilepsies. In this article we review what has been learned about cellular mechanisms and potential new therapies from these model systems, with a particular emphasis on the novel model system of knock in Drosophila and a look toward the future with expanded use of patient-specific induced pluripotent stem cell-derived neurons.

Keywords: Drosophila; SCN1A; epilepsy; iPSC; model systems.

Fig. 1.

A: schematic of the structure of a voltage-gated sodium channel α-subunit. Each of the 4 domains (I–IV) contains 6 transmembrane segments (S1–S6, from left to right). Plus sign (+) columns indicate voltage-sensing transmembrane segment S4 in each domain; S5 and S6 form the channel pore (black). The locations of the 7 SCN1A mutations that are referred to in this review are denoted by symbols. B: aligned amino acid sequence from the transmembrane segment S1 to S2 in domain III (DIII) of human, mouse, zebrafish, and fruit fly (Drosophila). The locations of the S1231R (solid circle) and K1270T (solid triangle) mutations are indicated by arrows.

Fig. 2.

A and B: representative trains of evoked spikelets recorded from control, Dravet syndrome (DS), and genetic epilepsy with febrile seizures plus (GEFS+) local neurons (LNs) at 23 and 35°C. Arrow indicates the poststimulus depolarization in GEFS+ LNs at 35°C. C: spikelet frequency plotted as a function of injected current for the LNs shown above. [Modified from Sun et al. 2012 and Schutte et al. 2014 with permission.]

Fig. 3.

A and B: representative trains of evoked spikelets recorded from control, DS, and GEFS+ motor neurons (MNs) at 23 and 35°C. C: average spikelet frequency plotted as a function of injected current for control, DS, and GEFS+ MNs. Symbols and error bars represent means ± SE from the number (n) of MNs indicated.

Fig. 4.

Comparison of peak firing frequency of LNs vs. MNs at 23 and 35°C in control, DS, and GEFS+ flies. Symbols and error bars represent means ± SE from the number (n) of neurons indicated.