Abstracts

Rationale: Oxytocin (OT) plays a role in cognitive, social, and neuroendocrine function, demonstrating that it has wide-spread effects in the brain. OT has also been identified as potentially therapeutic in neurological disorders such as autism and depression, which are often comorbid with epilepsy, raising the possibility that it might confer protection against the behavioral and seizure phenotypes in epilepsy. De novo loss-of-function mutations in the voltage-gated sodium channel SCN1A (encoding Na_v1.1) are the main cause of Dravet syndrome (DS), a catastrophic early-life encephalopathy associated with prolonged and recurrent early-life febrile seizures (FSs), refractory afebrile epilepsy, cognitive and behavioral deficits, and a 15-20% mortality rate. SCN1A mutations also lead to genetic epilepsy with febrile seizures plus (GEFS+), which is an inherited disorder characterized by early-life FSs and the development of a variety of adult epilepsy subtypes. Despite the wide range of antiepileptic drugs (AEDs) available, many of these patients remain resistant to treatment, thus identifying the need to develop more efficacious treatments. Heterozygous Scn1a knock-in mice expressing the human SCN1A epilepsy mutation R1648H (Scn1a^RH/+, a model of GEFS+) recapitulate many of the clinical features found in patients with DS and GEFS+, and thus provide an important opportunity to develop more efficacious AEDs. Methods: We first generated a ¼ log dose-response curve for OT (intracerebroventricular, i.c.v.) using the 6 Hz seizure induction paradigm in CF1 wild-type (WT) mice. We found that a dose of 10 mg OT increased resistance to 6 Hz-, but not pentylenetetrazole (PTZ)-induced seizures in CF1 mice. Results: We next transitioned into the Scn1a^RH/+ mutants and found that 10 mg OT (i.c.v.) provided significant protection against both 6 Hz- and PTZ-induced seizures. Since administration of OT directly into the brain conferred such robust seizure protection, we next evaluated the effect of intranasal administration of OT as this is a common clinical route for the delivery of OT. We found that intranasal delivery of OT (10 mg) was also capable of increasing resistance to 6 Hz-induced seizures in Scn1a^RH/+ mutants. We are currently evaluating the effect of OT in other seizure induction paradigms. Conclusions: This is the first study to provide evidence for oxytocin as a therapeutic strategy in Scn1a-derived epilepsy, and, by extension, other forms of refractory epilepsy. Funding: This work was supported by the American Epilepsy Society Postdoctoral Research Fellowship (JCW) and the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (AE and KSM, R21NS100512).