The Role of Stress and HPA Axis Dysfunction on Psychiatric Comorbidities and Seizure-Induced Death in a Rodent Models of Epilepsy
Abstract number :
1.573
Submission category :
1. Basic Mechanisms / 1E. Models
Year :
2025
Submission ID :
1326
Source :
www.aesnet.org
Presentation date :
12/6/2025 12:00:00 AM
Published date :
Authors :
Presenting Author: Katelyn Joyal, PhD – Tufts University School of Medicine
Tauryn Dargan, MS – Tufts University School of Medicine
Trina Basu, PhD – Tufts University School of Medicine
Jamie Maguire, PhD – Tufts University School of Medicine
Rationale: Psychiatric comorbidities are extremely common in patients with epilepsy. Emerging evidence suggests that dysfunction in the hypothalamic-pituitary-adrenal (HPA) axis dysfunction contributes to both psychiatric comorbidities and seizure mortality. Previous work from our laboratory demonstrated that mice with HPA axis dysfunction exhibit increased vulnerability to sudden unexpected death in epilepsy (SUDEP). To assess this relationship across models, we hypothesized that the Scn1b-/- mouse model that exhibits seizure-induced death may also exhibit HPA-axis dysfunction. We further hypothesized that chronic stress facilitates seizure-induced death in animals with HPA-axis dysfunction, and stimulation of CRH neurons in the paraventricular nucleus of the hypothalamus (PVN) will induce SUDEP in WT mice with pharmacologically-induced chronic epilepsy.
Methods: (1) Scn1b+/- mice were paired to produce Scn1b+/+, Scn1b+/-, and Scn1b-/- progeny. On postnatal day 14, the pups were sacrificed, and trunk blood was collected for plasma extraction. An ELISA was used to measure plasma corticosterone (CORT) from the WT, heterozygous, and null mutant animals. (2) Adult WT (Cre-/-) and Kcc2/Crh KO mice which exhibit HPA-axis hyperexcitability received a unilateral injection of 20 mM kainic acid (KA) into the ventral hippocampus to render them chronically epileptic. They then underwent 3 weeks of chronic unpredictable stress (CUS). The surviving mice underwent behavioral testing, including the open field test (OF), light/dark box (LD), and forced swim test. (3) Adult CRH-Cre mice received a unilateral injection of AAV-hSyn-DIO-hM4Dq-mCherry into the PVN to stimulate CRH neuron activity and were rendered chronically epileptic using the same methods stated above. They were also fitted with an EEG headmount and, following recovery, underwent chronic EEG recording for 28 days. Mice either received clozapine-N-oxide (CNO-) dissolved in their drinking water or normal drinking water. Seizure frequency and mortality were monitored during the recording period.
Results: (1) Scn1b-/- pups, which have been documented to universally experience seizure induced death by P26, had elevated plasma CORT levels compared to WT and heterozygous littermates. (2) Kcc2/Crh KO animals, which represent a model of HPA-axis dysfunction, experienced seizure-induced death following CUS while their WT littermates and Cre-/- animals did not. Male Kcc2/Crh KO mice that underwent CUS exhibited increased anxiety phenotypes during OF and LD testing, while female KOs exhibited increased stress-induced helplessness in the forced swim test. (3) Chemogenetic stimulation of PVNCRH neurons in chronically epileptic WT animals significantly increased the instance of seizure-induced death without affecting seizure burden.
Conclusions: Our results further implicate HPA-axis dysfunction as a shared underlying pathophysiology of SUDEP and psychiatric comorbidities in epilepsy. They also suggest that an underlying derangement in the HPA-axis is required for stress to trigger seizure-induced death, and that there are sex-based differences in potential psychiatric outcomes to chronic stress in epilepsy.
Funding: R01NS102937
Basic Mechanisms