Lateralized phenotypic differences in females in the intrahippocampal kainic acid mouse model of temporal lobe epilepsy

Abstract

Clinical evidence indicates that patients with temporal lobe epilepsy (TLE) often show differential outcomes of comorbid conditions dependent on the lateralization of the seizure focus. However, whether a left or right seizure focus produces differential effects on comorbid outcomes has not been investigated in a rodent model of chronic recurrent seizures. Here, we used the intrahippocampal kainic acid (IHKA) mouse model of TLE to determine whether targeting of left or right dorsal hippocampus for injection produces different outcomes in hippocampal sclerosis, body weight gain, and multiple measures of reproductive endocrine dysfunction in female mice. At one, two, and four months after injection, in vivo measurements of estrous cycles and weight were followed by ex vivo examination of hippocampal sclerosis, circulating ovarian hormone and corticosterone levels, ovarian morphology, and pituitary gene expression. IHKA mice with right-targeted injection (IHKA-R) showed greater granule cell dispersion and pituitary Fshb expression compared to mice with left-targeted injection (IHKA-L). By contrast, pituitary expression of Lhb and Gnrhr were higher in IHKA-L mice compared to IHKA-R, but these values were not different from respective saline-injected controls. IHKA-L mice also showed an increased rate of weight gain compared to IHKA-R mice. Disruptions to estrous cyclicity, however, were similar in both IHKA-L and IHKA-R mice. These findings indicate that although major reproductive endocrine dysfunction phenotypes present similarly after targeting left or right dorsal hippocampus in the IHKA model of TLE, distinct latent mechanisms based on lateralization of seizure focus may contribute to produce similar emergent reproductive endocrine outcomes. Significance Statement People with epilepsy often develop comorbidities dependent on the side of the brain in which the seizures originate. However, the mechanisms linking laterality of seizure initiation side to different comorbidities are unknown. Here, we examined whether injection of kainic acid in the left or right hippocampus, a model of temporal lobe epilepsy, produces differential effects on hippocampal damage, weight gain, and measurements of female reproductive endocrine function in female mice. We found that hippocampal sclerosis, pituitary gene expression, and weight gain are influenced by the side of injection. These results are the first demonstration of changes in pituitary gene expression in a model of epilepsy and indicate that the hemisphere targeted in the intrahippocampal kainic acid model impacts phenotypic outcomes.