Abstracts

Rationale: Psychiatric disorders are highly comorbid in people with epilepsy (PWE), with a high incidence of depression (55%) and anxiety (25-50%) (Lambert, 1999; Brandt, 2013). These comorbidities negatively impact their quality of life and, if left untreated, can severely worsen the course of epilepsy. The mechanisms underlying psychiatric comorbidities in epilepsy remain unclear.

Hypothalamic-pituitary-adrenal (HPA) axis hyperactivity is a cardinal feature of depression, evident from elevated corticotropin releasing hormone (CRH) and cortisol levels. HPA axis dysfunction can exacerbate neuropathology and disease progression in epilepsy. Activation of the HPA axis accelerates epileptogenesis (Wulsin, et al., 2018; Jones, et al., 2013) and cortisol can be proconvulsant (Joels, 2009). Cortisol levels are basally elevated in PWE, further increased following a seizure, and correlates with seizure severity (Culebras, 1987; Galimberti, et al., 2005). We have shown that seizures activate the HPA axis, and this contributes to increased seizure susceptibility in temporal lobe epilepsy (TLE) (O’Toole, 2013). These studies indicate a bidirectional relationship between mood disorders and epilepsy, suggesting that the comorbidity may be driven by HPA axis dysregulation.

Methods: Seizure induced HPA axis activation results from the downregulation in the expression and function of the K⁺/Cl^- cotransporter, KCC2, in CRH neurons (O’Toole, 2013). Mice that lack KCC2 in CRH neurons (KCC2/CRH) show an exaggerated seizure induced HPA axis activation. Chronically epileptic KCC2/CRH and control mice were used to study whether seizure-induced HPA axis hyperactivation worsens epilepsy outcomes.

2 weeks post-SE, we recorded EEG activity from these mice for 21 days. Mice underwent a battery of anxiety- and depression-like behavioral tests 60 days post-SE. Brains were collected for post-mortem analysis of neuropathology.

Human hypothalamic tissue and blood samples (from control, PWE, and SUDEP subjects) were obtained from the North American SUDEP Registry. Tissue was sectioned and stained for CRH transcript expression through RNAscope. Human blood samples underwent ELISAs for cortisol, CRH, ACTH, norepinephrine, and epinephrine.

Results: Chronically epileptic KCC2/CRH mice exhibit sex specific differences in seizure burden, greater vulnerability to affective states, and exacerbated neuropathology compared to control mice. About 40% of male KCC2/CRH mice die immediately following a seizure event, suggesting that HPA axis dysregulation may contribute to SUDEP and the KCC2/CRH mice may be a novel, non-genetic model of SUDEP. Attenuating HPA axis hyperactivation reduces seizure burden in epileptic KCC2/CRH mice. ELISA analysis of cortisol (corticosterone in mice), CRH, ACTH, norepinephrine, and epinephrine suggest that persistent and excessive HPA axis activity in chronic epilepsy may lead to a collapse in its regulation, leading to increased risk for mood disorders and SUDEP.

Conclusions: Therapeutically targeting the HPA axis may be beneficial in slowing disease progression, alleviating comorbid affective disorders in PWE, and reducing risk of SUDEP.

Funding: Please list any funding that was received in support of this abstract.: SRO1NS102937-02.