Lateralized phenotypic differences after intrahippocampal kainic acid injection in female mice

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.

Epilepsy-associated increase in gonadotropin-releasing hormone neuron firing in diestrous female mice is independent of chronic seizure burden severity

“…It is thus possible that seizure focus location, rather than epilepsy severity, is more determinative in shaping the type and degree of reproductive endocrine comorbidities in patients with TLE. In recent studies examining the effect of targeting left or right hippocampus for KA injection in mice, however, we observed similar increases in estrous cycle length regardless of injection site lateralization (Cutia et al, 2021). Likewise, no differences in estrous cycle disruption dependent on left-vs. right-sided seizure focus location were observed in a rat amygdala kindling model (Hum et al, 2009).…”