Contributions of gonadal hormones vs. sex chromosomes in shaping sex differences in epilepsy

PROJECT SUMMARY Sex differences are present in many forms of epilepsy, both in humans and in preclinical animal models. The origins of these sex differences remain poorly understood. Although gonadal hormones strongly influence neural excitability and seizure activity in both males and females, the contributions of sex chromosomes, the other component of biological sex, in driving differences in seizures between and within sexes are largely unknown. The studies in this project will apply a unique mouse model, in which gonadal and chromosomal sex effects can be dissociated, to the study of seizures and epilepsy for the first time. Using a combination of in vivo video-electroencephalography, RNA sequencing, and immunostaining, we will determine the contributions of sex chromosomes and gonadal hormones in shaping acute seizure susceptibility and seizure-induced neuropathology (Aim 1) and spontaneous recurrent seizures and hippocampal gene expression in a mouse model of chronic temporal lobe epilepsy (Aim 2). This work will have positive translational impact by addressing the 2021 NINDS Epilepsy Research Benchmark to “identify and understand mechanisms of sex modulation of epilepsy risk,” and will provide a basis for future mechanistic investigations of the interactions between sex chromosomes and specific gonadal hormones in shaping neural excitability, seizures, and epilepsy in both males and females.