Sex-related Differences in Glial Fibrillary Acidic Protein-positive GABA Regulate Neuropathology Following Pilocarpine-induced Status Epilepticus

Abstract

Status epilepticus (SE) is a life-threatening neurological disorder that causes neuronal death and glial activation. Studies have explained the clinical side effects and lack of effectiveness of neurological disorder treatments based on sex-related differences in brain structure and function. However, the sex-specific outcomes of seizure disorders and the underlying mechanisms remain unknown. We compared SE-induced behavioral and pathophysiological changes in male and female mice. The time taken to reach stage 6 seizure following pilocarpine injection was shorter in male mice than in female mice, and the prevalence of SE was higher in male mice than in female mice. Fluoro-Jade B staining revealed more extensive SE-induced hippocampal neuronal death in male mice than in female mice. Glial cells were more activated in male mice than in female mice. In contrast, astrocyte-derived γ-aminobutyric acid (GABA)-immunostaining was less expressed in male mice than in female mice. Moreover, the mRNA levels of inflammatory cytokines released from activated glial cells were higher in male mice than in female mice. Notably, the mRNA level of astrocytic γ-aminobutyric acid transporter (GAT-3) involved in extracellular GABA uptake was lower in female mice than in male mice, while the mRNA levels of glutamate/aspartate transporter (GLAST (EAAT1)) and glutamate transporter (GLT-1 (EAAT2)) involved in extracellular glutamate uptake were higher in female mice. Our findings suggest that male mice are more vulnerable to SE than female mice, resulting in more extensive neuronal cell death and glial activation in male mice, partly due to increased GAT-3 expression that subsequently leads to reduced glial fibrillary acidic protein (GFAP)-positive GABA content assessed with anti-GABA antibodies.