Sex and estrous cycle stage shape left-right asymmetry in chronic hippocampal seizures in mice

Abstract

Lateralization of hippocampal function is indicated by varied outcomes of patients with neurological disorders that selectively affect one hemisphere of this structure, such as temporal lobe epilepsy (TLE). The intrahippocampal kainic acid (IHKA) injection model of TLE allows for targeted damage to the left or right hippocampus, enabling systematic comparison of effects of left-right asymmetry on seizure and non-seizure outcomes. Although varying non-seizure phenotypic outcomes based on injection side in dorsal hippocampus were recently evaluated in this model, differences in chronic seizure patterns in left- (IHKA-L) vs. right-injected (IHKA-R) IHKA animals have yet to be evaluated. Here, we evaluated hippocampal seizure incidence in male and female IHKA-L and IHKA-R mice. Females displayed increased electrographic seizure activity compared to males at both 2 months and 4 months post-injection (mpi). In addition, IHKA-L females showed higher seizure frequency than IHKA-R on diestrus and estrus at 2 mpi, but seizure duration and time in seizures were only higher in IHKA-L females on diestrus. These cycle stage-associated changes, however, did not persist to 4 mpi. Furthermore, this lateralized difference in seizure burden was not observed in males. These results indicate for the first time that the side of IHKA injection can shape chronic electrographic seizure burden. Overall, these results demonstrate a female-specific left-right asymmetry in hippocampal function can interact with estrous cycle stage to shape chronic seizures in mice with epilepsy, with implications for neural activity and behavior in both normal and disease states.

Sex and gonadectomy modify behavioral seizure susceptibility and mortality in a repeated low‐dose kainic acid systemic injection paradigm in mice

“…1 In animal models, several studies have documented sex differences in acute seizure susceptibility or chronic epilepsy presentation, although the directionality of the sex effect can vary by model and species. [6][7][8][9][10][11][12][13][14] Many of these sex differences are likely a result of distinct neural effects of gonadal hormones in males and females. 1,[14][15][16] Both estrogen and progesterone have proconvulsant and anticonvulsant effects, as documented in studies examining different species and models of seizure and epilepsy induction.…”