Sex differences in SUDEP susceptibility: the role of progesterone and estradiol

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Project Abstract: Epilepsy is one of the most common neurological diseases worldwide. Despite a large number of available antiepileptic drugs (AEDs), more than one-third of people with epilepsy are not able to control their seizures with medication, putting them at higher risk for sudden unexpected death in epilepsy (SUDEP). SUDEP is a major cause of death in patients with drug-resistant epilepsy, and while it is distributed across all ages and affects both males and females, it is more prevalent in males. In some epileptic females, seizure frequency and severity are known to fluctuate, corresponding to changes in sex steroid levels. Possibly, sex steroids play a role in the regulation of seizures and might account for the sex difference in SUDEP incidence. To evaluate the role of sex steroids in seizure and SUDEP susceptibility, we used acute and chronic treatment of progesterone and estradiol (P+E) in a mouse model of Dravet Syndrome (DS) with a Scn1aR1407X/+ loss-of-function mutation. Our preliminary data demonstrate that SUDEP incidence and the seizure phenotype are improved in female and male mice acutely treated with P+E. Defects in the serotonin (5-HT) system and deficits in GABAergic function are associated with seizures and SUDEP. Animal studies have shown that acute and chronic treatment with P+E can increase 5-HT concentration in the brain and increase tonic GABA inhibition in the hippocampus. Further, sex steroids are known to stimulate breathing, potentially providing a method to rescue the respiratory phenotype observed in DS mice. Thus, we will test the working hypotheses that 1) P+E decrease SUDEP incidence by reducing seizure frequency and/or severity, and stimulating breathing, and 2) the anticonvulsant effects of P+E are mediated by serotonin and/or GABA. The effect of chronic and acute P+E treatment on seizures, SUDEP incidence, and breathing will be assessed through video- EEG/EKG monitoring of spontaneous and hyperthermia-induced seizures. Using DS mice in which 5- HT neurons have been genetically deleted, I will determine whether serotonin mediates the anticonvulsant effects conferred by acute and chronic P+E treatment. Lastly, I will assess for differences in GABA-A mediated tonic inhibition in the hippocampal slice of DS mice compared to wild type with and without acute application of P+E, or their metabolites, using whole-cell patch-clamp recordings. The proposed work will provide clearer insight into the role of sex steroids in SUDEP incidence. Further, as sex differences in seizure susceptibility are a widespread concern in epilepsy, identifying how sex steroids impact the serotonergic and GABAergic neural pathways, could provide clinicians with more effective treatment strategies for both male and female epilepsy patients.