Hypothalamic-Pituitary-Adrenal Axis Dysfunction Elevates SUDEP Risk in a Sex-Specific Manner.

Area of Science:

• Neuroscience
• Endocrinology
• Psychiatry

Background:

• Epilepsy frequently co-occurs with psychiatric disorders such as anxiety and depression.
• The underlying mechanisms linking epilepsy and psychiatric comorbidities, particularly involving the hypothalamic-pituitary-adrenal (HPA) axis, remain under-investigated.
• Stress is a known trigger for both epilepsy and depression, suggesting a role for HPA axis dysfunction.

Purpose of the Study:

• To investigate the role of HPA axis dysfunction in epilepsy outcomes and psychiatric comorbidities.
• To examine the impact of HPA axis dysfunction on seizure burden, behavioral deficits, and sudden unexpected death in epilepsy (SUDEP) in a novel mouse model.

Main Methods:

• Generated a novel mouse model (Kcc2/Crh KO mice) with impaired KCC2 cotransporter in CRH neurons, leading to HPA axis hyperactivation.
• Assessed seizure frequency/burden, comorbid behavioral deficits, and SUDEP risk in Kcc2/Crh KO mice.
• Utilized pharmacological and chemogenetic approaches to suppress HPA axis hyperexcitability and analyzed neuroendocrine markers in SUDEP cases.

Main Results:

• Found sex differences in the effects of HPA axis dysfunction on seizure burden, behavioral deficits, and SUDEP in Kcc2/Crh KO mice.
• Suppression of HPA axis hyperactivity reduced SUDEP incidence in the mouse model.
• Identified altered neuroendocrine markers in SUDEP cases compared to controls.

Conclusions:

• HPA axis dysfunction is implicated in the pathophysiology of psychiatric comorbidities in epilepsy.
• HPA axis dysfunction may contribute to SUDEP.
• The findings highlight the interconnectedness of the HPA axis, epilepsy, psychiatric comorbidities, and SUDEP.