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

• Type of Material: Article
• Authors: Nikki T Sawyer, Emory University; Ligia A Papale, Emory University; Jessica Eliason, Emory University; Gretchen Neigh, Emory University; Andrew Escayg, Emory University
• Language: English
• Date: 2014-01-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 Elsevier Ltd. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.psyneuen.2013.09.018
• Title of Journal or Parent Work: Psychoneuroendocrinology
• ISSN: 0306-4530
• Volume: 39
• Issue: 1
• Start Page: 225
• End Page: 236
• Grant/Funding Information: Research in this publication was supported by the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH) under award numbers R01NS07221 (AE) and F31NS073237 (NTS).; Support was also provided by an ARCS Fellowship (NTS).
• Keywords: Scn8a; Absence; Endocrinology & Metabolism; ABSENCE EPILEPSY; Anxiety; Neurosciences; FACTOR CRF; NEURONS; PERCEPTION; PHENOTYPES; BEHAVIOR; Psychiatry; Life Sciences & Biomedicine; FREQUENCY; PRECIPITANTS; MODEL; Seizures; Epilepsy; Science & Technology; Stress; SPIKE-WAVE DISCHARGES; Neurosciences & Neurology
• Research Categories: Psychology, Behavioral; Biology, Physiology; Biology, Genetics

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 (1700-1900. h). A 20-min 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 3. h 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-min 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.