RT Journal Article
SR Electronic
T1 Hypothalamic–Pituitary–Adrenal Axis Dysfunction Elevates SUDEP Risk in a Sex-Specific Manner
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0162-24.2024
DO 10.1523/ENEURO.0162-24.2024
VO 11
IS 7
A1 Basu, Trina
A1 Antonoudiou, Pantelis
A1 Weiss, Grant L.
A1 Coleman, Emanuel M.
A1 David, Julian
A1 Friedman, Daniel
A1 Laze, Juliana
A1 Strain, Misty M.
A1 Devinsky, Orrin
A1 Boychuk, Carie R.
A1 Maguire, Jamie
YR 2024
UL http://www.eneuro.org/content/11/7/ENEURO.0162-24.2024.abstract
AB Epilepsy is often comorbid with psychiatric illnesses, including anxiety and depression. Despite the high incidence of psychiatric comorbidities in people with epilepsy, few studies address the underlying mechanisms. Stress can trigger epilepsy and depression. Evidence from human and animal studies supports that hypothalamic–pituitary–adrenal (HPA) axis dysfunction may contribute to both disorders and their comorbidity ( Kanner, 2003). Here, we investigate if HPA axis dysfunction may influence epilepsy outcomes and psychiatric comorbidities. We generated a novel mouse model (Kcc2/Crh KO mice) lacking the K+/Cl− cotransporter, KCC2, in corticotropin-releasing hormone (CRH) neurons, which exhibit stress- and seizure-induced HPA axis hyperactivation ( Melon et al., 2018). We used the Kcc2/Crh KO mice to examine the impact on epilepsy outcomes, including seizure frequency/burden, comorbid behavioral deficits, and sudden unexpected death in epilepsy (SUDEP) risk. We found sex differences in HPA axis dysfunction’s effect on chronically epileptic KCC2/Crh KO mice seizure burden, vulnerability to comorbid behavioral deficits, and SUDEP. Suppressing HPA axis hyperexcitability in this model using pharmacological or chemogenetic approaches decreased SUDEP incidence, suggesting that HPA axis dysfunction may contribute to SUDEP. Altered neuroendocrine markers were present in SUDEP cases compared with people with epilepsy or individuals without epilepsy. Together, these findings implicate HPA axis dysfunction in the pathophysiological mechanisms contributing to psychiatric comorbidities in epilepsy and SUDEP.