Extrasynaptic γ-aminobutyric acid type A receptor-mediated sex differences in the antiseizure activity of neurosteroids in status epilepticus and complex partial seizures

Objective Sex differences are evident in the antiseizure activity of neurosteroids; however, the potential mechanisms remain unclear. In this study, we sought to determine whether differences in target extrasynaptic delta-subunit gamma-aminobutyric acid type A (GABA-A) receptor expression and function underlie the sex differences in seizure susceptibility and the antiseizure activity of neurosteroids. Methods Sex differences in seizure susceptibility and protective activity of three distinct neurosteroids-allopregnanolone (AP), androstanediol (AD), and ganaxolone-were evaluated in the pilocarpine model of status epilepticus (SE) and kindling seizure test in mice. Immunocytochemistry was used for delta GABA-A receptor expression analysis, and patch-clamp recordings in brain slices evaluated its functional currents. Results Sex differences were apparent in kindling epileptogenic seizures, with males exhibiting a faster progression to a fully kindled state. Neurosteroids AP, AD, or ganaxolone produced dose-dependent protection against SE and acute partial seizures. However, female mice exhibited strikingly enhanced sensitivity to the antiseizure activity of neurosteroids compared to males. Sex differences in neurosteroid protection were unrelated to pharmacokinetic factors, as plasma levels of neurosteroids associated with seizure protection were similar between sexes. Mice lacking extrasynaptic delta GABA-A receptors did not exhibit sex differences in neurosteroid protection. Consistent with a greater abundance of extrasynaptic delta GABA-A receptors, AP produced a significantly greater potentiation of tonic currents in dentate gyrus granule cells in females than males; however, such enhanced AP sensitivity was diminished in delta GABA-A receptor knockout female mice. Significance Neurosteroids exhibit greater antiseizure potency in females than males, likely due to a greater abundance of extrasynaptic delta GABA-A receptors that mediate neurosteroid-sensitive tonic currents and seizure protection. These findings indicate the potential to develop personalized gender-specific neurosteroid treatments for SE and epilepsy in men and women, including catamenial epilepsy.