Comparison of kainate-induced seizures, cognitive impairment and hippocampal damage in male and female mice

Abstract

Kainate (KA) mouse model induced by intraperitoneal injection has been widely used for epilepsy and neurodegeneration studies. KA elicits sustained epileptic activity in mouse brain revealed by recurrent behavioral seizures, deteriorative neurodegeneration and various neurological deficits. However, to date, the vast majority of the studies used male mice only, and few studies on the comparison of brain injury between male and female mice in this model were reported. Epidemiological studies indicate that sex may affect the susceptibility to seizure response and neurodegeneration process. Therefore, this study focused on the effect of sex difference on KA-induced recurrent seizures and mortality, locomotor activity and cognitive impairment, and hippocampal neurodegeneration and reactive gliosis in mice. Our results showed that, compared to females, adult male mice exhibited worse performance in mortality rate, severity of epileptic seizures, and cognitive impairment indicated by novel object recognition task. Unexpectedly, post-KA male and female mice underwent similar decline and recovery of locomotor activity. KA-induced neurodegeneration in the whole hippocampus, particularly in CA1 and CA3 subregions, along with the deteriorative reactive gliosis in astrocytes and microglia, was more severe in males than that in females. These data provided the direct in vivo evidence that indicates the key role of sex difference in studies with KA mouse model, and this could be beneficial for optimizing the design of future studies.