Scn8a voltage-gated sodium channel mutation alters seizure and anxiety responses to acute stress

Abstract

Stress is known to trigger seizures in patients with epilepsy, highlighting the physiological stress response as a possible therapeutic target for epilepsy treatment. Nevertheless, little is currently known about how a genetic predisposition to epilepsy interacts with the stress response to influence seizure outcome. To address this question, we examined the effect of acute stress on seizure outcome in mice with mutations in the voltage-gated sodium channel (VGSC) gene Scn8a. Scn8a mutants display spontaneous spike-wave discharges (SWDs) characteristic of absence epilepsy. We saw that the baseline frequency of SWDs in Scn8a mutants correlates closely with the diurnal activity of the hypothalamic-pituitary-adrenal (HPA) axis, with a peak in seizure activity occurring at around the same time as the peak in corticosterone (1700h–1900h). A 20-minute acute restraint stress administered in the morning increases the frequency of spontaneous SWDs immediately following the stressor. Seizure frequency then returns to baseline levels within three hours after stressor exposure, but the subsequent evening peak in seizure frequency is delayed and broadened, changes that persist into the next evening and are accompanied by long-lasting changes in HPA axis activity. Scn8a mutants also show increased anxiety-like behavior in mildly stressful situations. A 20-minute acute restraint stress can also increase the severity and duration of chemically induced seizures in Scn8a mutants, changes that differ from wild-type littermates. Overall, our data show that a voltage-gated sodium channel mutation can alter the behavioral response to stress and can interact with the stress response to alter seizure outcome.

An Scn1a epilepsy mutation in Scn8a alters seizure susceptibility and behavior

“…Scn8a mutations have been associated with alterations in anxiety in mice (McKinney et al, 2008; Sawyer et al, 2014) and psychiatric and cognitive deficits in humans (Trudeau et al, 2006; Wang et al, 2008; Wasserman et al, 2005). However, anxiety levels, as measured by the percentage of time spent in the open arm or the number of entries into the open arm of an elevated plus maze, were comparable between Scn8a RH/+ , Scn8a RH/RH and WT littermates (Table 1).…”

SCN3A deficiency associated with increased seizure susceptibility

“…Seizure induction using flurothyl (2,2,2-trifluroethyl ether, Sigma-Aldrich) was performed as previously described (Makinson et al, 2014; Martin et al, 2007; Sawyer et al, 2014). Briefly, 5–8 week old Scn3a +/ Hyp male and female mutants (n = 29/sex) and WT littermates (male n = 33; female n = 32) were placed in a clear chamber and flurothyl was introduced at a constant rate of 20 μl/min.…”

Role of Sodium Channels in Epilepsy

“…A substantial proportion of these mutations are in VGSCs genes with the vast majority discovered in SCN1A , and fewer in SCN2A , SCN8A, and SCN1B (Wallace et al 1998; Wallace et al 2002; Mulley et al 2005; Striano et al 2006; Herlenius et al 2007; Patino et al 2009; Shi et al 2009; Allen et al 2013; O’Brien and Meisler 2013; Sawyer et al 2014). …”