Effects of lateralized hippocampal damage and pituitary gonadotrope dysfunction in a mouse model of temporal lobe epilepsy

Reproductive endocrine dysfunction is a common comorbidity of temporal lobe epilepsy (TLE). The specific mechanisms that link temporal lobe seizures to reproductive endocrine dysfunction remain unknown. However, clinical reports suggest that epilepsy-associated hypothalamic-pituitary-gonadal (HPG) axis dysfunction likely underlies the development of reproductive endocrine disorders. The intrahippocampal kainic acid (IHKA) mouse model of TLE also shows reproductive endocrine dysfunction as a majority of female IHKA treated animals display estrous cycle disruption. Furthermore, IHKA mice display alterations in the HPG axis as the activity of, and input to, hypothalamic gonadotropin-releasing hormone (GnRH) neurons is changed in IHKA females that develop estrous cycle elongation. However, further work in this model is needed to identify a specific mechanism that links the epilepsy-associated changes in hypothalamic circuitry to the development of reproductive endocrine dysfunction. The overall goal of this dissertation is to evaluate the progression and robustness of the reproductive endocrine dysfunction phenotype in female IHKA mice and to determine if epilepsy-associated hypothalamic changes in this model impact the pituitary. Chapter 2 investigates the differences in the presentation and progression of pituitary and gonadal phenotypic outcomes in female mice injected in the left vs. right dorsal hippocampus with KA. Chapter 3 continues to investigate the impacts of IHKA injection site by characterizing seizure burden differences in the left vs. right IHKA mice. Chapter 4 investigates the epilepsy-associated changes in pituitary release of gonadotropins and sensitivity to GnRH. The results from Chapter 2 and 3 indicate that the side of IHKA injection does not impact the development of comorbid estrous cycle disruption in females, but that KA injection site can impact pituitary gene expression and seizure burden in a sex- and estrous cycle-dependent manner. The results from Chapter 4 indicate that there are epilepsy-associated elevations in pituitary sensitivity to GnRH on certain estrous cycle stages in the absence of changes to the pattern of gonadotropin release. Overall, the data in this dissertation demonstrate that, within the IHKA model, lateralization of hippocampal damage can have implications on phenotypes present, and that temporal lobe seizures lead to altered pituitary function. This data demonstrates the usefulness of the IHKA model in the study of mechanisms linking temporal lobe seizures to altered reproductive endocrine function and vice versa.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Neuroscience

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2023

Author dc:creator

• Cutia, Cathryn A

Contributors dc:contributor

• Christian-Hinman, Catherine
• Llano, Daniel
• Raetzman, Lori
• Gritton, Howard

• Reproductive Endocrine Dysfunction
• Mouse Model
• Temporal Lobe Epilepsy

Statement dc:rights

• Copyright 2023 Cathryn Cutia

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/121965

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F121965