Abstracts

Seizure Induced Hyperactivation of the HPA Axis Exacerbates Neuropathology Associated with Epileptogenesis and Contributes to Affective States in Epilepsy.

Abstract number : 3.053
Submission category : 1. Basic Mechanisms / 1D. Mechanisms of Therapeutic Interventions
Year : 2019
Submission ID : 2421952
Source : www.aesnet.org
Presentation date : 12/9/2019 1:55:12 PM
Published date : Nov 25, 2019, 12:14 PM

Authors :
Trina Basu, Tufts University School of Medicine; Jamie L. L. Maguire, Tufts University School of Medicine

Rationale: Stress is the most common, self-reported trigger preceding a seizure in epilepsy patients. The body’s physiological response to stress is mediated by the hypothalamic-pituitary-adrenal (HPA) axis. Stress provokes a cascade of events that begins by activating corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) of the hypothalamus and culminates in the synthesis and release of cortisol from the adrenal glands. Activation of the HPA axis has been shown to accelerate epileptogenesis (Wulsin, et al., 2016; Jones, et al., 2013; Salzberg, et al., 2007) and cortisol is generally considered to be proconvulsant (Joels, 2009). Epilepsy patients basally exhibit heightened circulating cortisol levels that are further increased following a seizure episode (Culebras, et al., 1987). Furthermore, increased seizure severity in patients has been shown to correlate with greater circulating cortisol levels (Galimberti, et al., 2005). Consistent with these data, our laboratory has recently shown that seizures activate the HPA axis, and this contributes to increased seizure susceptibility in two different chemoconvulsant models of temporal lobe epilepsy (TLE) (O’Toole, et al., 2013). These data suggest a role for the HPA axis in worsening seizure outcomes independent of stress.In addition to suffering from seizures, there is a high comorbidity of psychiatric disorders in epilepsy patients. Depression and anxiety are the two most common comorbidities associated with epilepsy, with incidence rates at 55% and 25-50%, respectively--higher than in any other patient population with a chronic illness (Lambert, et al., 1999; Brandt, et al., 2013). Hyperactivity of the HPA axis is a cardinal feature of affective states, such as depression and anxiety (Swaab, et al., 2005). The analogous increase in HPA axis activity in epilepsy and in affective disorders indicates a common mechanistic feature that may contribute to their comorbid appearance. We set forth to test the prediction that seizure induced activation of the HPA axis exacerbates neuropathology associated with epileptogenesis, increases seizure susceptibility, and contributes to the comorbid appearance of depression and/or anxiety in chronically epileptic mice. Methods: Recently, we demonstrated that the seizure induced activation of the HPA axis involved a downregulation in the expression and function of the K+/Cl- co-transporter, KCC2 in CRH neurons in the PVN (O’Toole, et al., 2013). In accordance with these findings, we generated mice that lack KCC2 in CRH neurons (KCC2/CRH). These mice exhibit an exacerbated seizure induced activation of the HPA axis. We utilized the ventral intrahippocampal kainic acid (vIHKA) model of TLE (Zeidler, et al., 2018) to induce status epilepticus (SE) in control and KCC2/CRH mice. Two weeks post-SE, we recorded electroencephalogram (EEG) activity from the cortex and the ventral hippocampus. We waited 60 days post-SE to put chronically epileptic control and KCC2/CRH mice through a battery of paradigms testing for anxiety- and depression-like behavior. Following EEG and behavioral testing, immunofluorescence for mossy fiber sprouting, dentate granule cell dispersion, and hilar cell loss were carried out. Results: Compared to chronically epileptic control mice, chronically epileptic KCC2/CRH mice exhibit increased seizure frequency, increased anxiety- and depression-like behavior, greater mortality, and exacerbated neuropathological features observed via immunofluorescence staining. Conclusions: We show that SE induced hyperactivation of the HPA axis contributes to an exacerbation of neuropathology associated with epileptogenesis. The results from this study furthers our understanding of how HPA axis activation contributes to epileptogenesis and comorbid affective states in epilepsy. Future experiments will be directed towards chemogenetically manipulating the activity of CRH neurons in the PVN to test how altering HPA axis activity contributes to the phenotypes we uncovered in the present study. Funding: NIH 5R01NS102937-03
Basic Mechanisms