Abstracts

Rationale:
    Stress is the most common, self-reported trigger for a seizure in epilepsy patients. The body’s response to stress is physiologically mediated by the hypothalamic-pituitary-adrenal (HPA) axis, which involves a cascade of events that begins by activating corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) of the hypothalamus and ends with the synthesis and release of cortisol from the adrenal glands.      Epileptogenesis is accelerated with HPA axis activation (Wulsin, 2018; Jones, 2013; Salzberg, 2007) and cortisol is generally considered to be a proconvulsant (Joels, 2009). People with epilepsy basally exhibit increased circulating cortisol, which is further elevated after a seizure (Culebras, 1987) and seizure severity correlates with greater circulating cortisol levels (Galimberti, 2005). We've shown that seizures activate the HPA axis, and this contributes to increased seizure susceptibility in two distinct models of temporal lobe epilepsy (TLE) (O’Toole, 2013). The results of our study suggest a role for HPA axis in worsening seizure outcomes independent of stress.      Depression and anxiety are the two most common comorbidities associated with epilepsy (Lambert, 1999; Brandt, 2013). Hyperactivity of the HPA axis is a cardinal feature of affective states (Swaab, 2005). The analogous increase in HPA axis activity in epilepsy and in affective disorders suggests a common mechanistic feature that may contribute to their comorbid appearance.       Here, we show that seizure induced activation of the HPA axis worsens neuropathology, exacerbates seizure burden, and increases vulnerability to affective states in chronically epileptic mice.  
Method:
     Seizure induced activation of the HPA axis involves a downregulation in the expression and function of the K+/Cl- co-transporter, KCC2 in CRH neurons in the PVN (O’Toole, 2013). We generated mice that lack KCC2 in CRH neurons (KCC2/CRH), which exhibit an exaggerated seizure induced activation of the HPA axis. To generate chronically epileptic mice, we injected kainic acid in the ventral hippocampus (Zeidler, 2018).      To test whether attenuating seizure induced HPA axis activation would lessen disease severity, a group of KCC2/CRH mice were implanted with RU486, a synthetic glucocorticoid antagonist (Peeters, 2004). Another group of KCC2/CRH mice were injected with hM4Di-DREADD in the PVN to inhibit CRH neurons.      Two weeks post-SE, we recorded electroencephalogram (EEG) activity for 21 days. Chronically epileptic mice underwent anxiety- and depression-like behavior paradigms 60 days post-SE. Mice were sacrificed and brains collected for post-mortem analysis of mossy fiber staining, dentate granule cell dispersion, and hilar cell loss.
Results:
Chronically epileptic KCC2/CRH mice show increased seizure burden, greater vulnerability to anxiety- and depression-like behaviors, and exacerbated neuropathology compared to control. About 40% of chronically epileptic KCC2/CRH mice died immediately after a seizure, suggesting that excessive HPA axis activation may be a risk factor for SUDEP and KCC2/CRH mice may be a novel model of SUDEP. Finally, attenuation of HPA axis dysfunction relieves seizure burden and reduces SUDEP occurrence.
Conclusion:
Seizure induced hyperactivation of the HPA axis contributes to the worsening of neuropathology, behavioral impairments, and seizure burden in chronically epileptic mice. We also find that attenuation of HPA axis dysfunction in chronically epileptic mice lessens seizure severity, suggesting a therapeutic intervention that can be utilized alongside anti-seizure medication to slow disease progression, and potentially alleviate comorbid affective states in patients with epilepsy.
Funding:
:NINDS