Human studies show a link between stress and epilepsy, with stress causing an increase in seizure frequency and severity in patients with epilepsy. While many different animal model systems have been used to better understand this connection and the possible mechanisms involved, results have not been clear. Furthermore, 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 relationship between stress and seizure outcome in two genetic models of epilepsy that carry mutations in voltage-gated sodium channels (VGSCs) Scn8a and Scn1a. Scn8amed/+ mutants display spontaneous absence seizures and an increased threshold to induced seizures. Scn1aRH/+ mutants exhibit spontaneous convulsive seizures and a reduced threshold to induced seizures. In the experiments described herein we demonstrate that the VGSC mutations can affect the stress response, seizure outcomes following either a stressor or altered early life experience, and behavior. Scn8amed/+ mutants respond to stress differently from their wildtype (WT) littermates, and higher levels of anxiety-like behaviors may be driving the seizure response to a stressor in this model. Stress also negatively affects the Scn1aRH/+ mutants, but in a similar manner to their WT littermates. The Scn8amed/+ line and Scn1aRH/+ line are maintained on different mouse strains, suggesting that genetic background and the presence of modifier genes may also affect the seizure response to a stressor. We also demonstrate that experiences encountered early in life can modify seizure outcome in adult animals in ways that depend on both the genetic makeup of the organism and sex of the organism. Overall, we show that altered neural excitability due to an epilepsy-causing mutation can affect the stress response, seizure outcomes following either a stressor or altered early life experience, and behavior. These results highlight the importance of using genetic models of epilepsy to better understand how stress is working to influence seizure activity.
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