Summary 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 both epilepsy and depression and significant accumulating evidence, from both human and animal studies, support that hypothalamic-pituitary-adrenal (HPA) axis dysfunction may contribute to the comorbidity of these two disorders 1 . Here we directly investigate the contribution of HPA axis dysfunction to epilepsy outcomes and psychiatric comorbidities. We generated a novel mouse model (KCC2/Crh mice) that lacks the K + /Cl - co-transporter, KCC2, in corticotropin-releasing hormone (CRH) neurons, which exhibit stress- and seizure-induced hyperactivation of the HPA axis. 2,3 Here we demonstrate that HPA axis dysfunction in KCC2/Crh mice is associated with increased vulnerability to behavioral deficits in chronically epileptic mice and more severe neuropathological features associated with chronic epilepsy (e.g. increased mossy fiber sprouting). Despite equivalent seizure burden, HPA axis dysfunction in these chronically epileptic mice increased the incidence of sudden unexpected death in epilepsy (SUDEP). Suppressing HPA axis hyperexcitability in this model using a pharmacological or chemogenetic approach decreased SUDEP incidence, supporting HPA axis dysfunction in SUDEP vulnerability. We also observed changes in neuroendocrine markers in individuals that died of SUDEP compared to people with epilepsy or individuals without a history of epilepsy. Together, these findings describe a novel, nongenetic mouse model of SUDEP which will benefit preclinical SUDEP research to gain a better understanding of the underlying pathological mechanisms contributing to SUDEP. HPA axis dysfunction increases vulnerability to psychiatric comorbidities in epilepsy and may be a risk factor for SUDEP.

Hypothalamic-pituitary-adrenal axis dysfunction worsens epilepsy outcomes and increases SUDEP risk