Seizure-induced activation of the HPA axis increases seizure frequency and comorbid depression-like behaviors

Abstract

Our laboratory recently demonstrated that seizures activate the hypothalamic-pituitary-adrenal (HPA) axis, increasing circulating levels of corticosterone (O'Toole et al., 2013). Given the well-established proconvulsant actions of corticosterone, we hypothesized that seizure-induced activation of the HPA axis may contribute to future seizure susceptibility. Further, since hypercortisolism is associated with depression, we propose that seizure-induced activation of the HPA axis may contribute to comorbid depression and epilepsy. To test this hypothesis, we generated mice lacking the GABAA receptor (GABAAR) δ subunit specifically in corticotropin-releasing hormone (CRH) neurons (Gabrd/Crh mice), which exhibit hyporeactivity of the HPA axis (Lee et al., 2014). Gabrd/Crh mice exhibit blunted seizure-induced elevations in corticosterone, establishing a useful tool to investigate the contribution of HPA axis dysfunction on epilepsy and associated comorbidities. Interestingly, Gabrd/Crh mice exhibit decreased acute seizure susceptibility following kainic acid (KA) administration. Furthermore, chronically epileptic Gabrd/Crh mice exhibit a decrease in both spontaneous seizure frequency and depression-like behaviors compared with chronically epileptic Cre littermates. Seizure susceptibility and associated depression-like behaviors can be restored to wild type levels by treating Gabrd/Crh mice with exogenous corticosterone. Similarly, chemogenetic activation of CRH neurons in the paraventricular nucleus (PVN) is sufficient to increase seizure susceptibility; whereas, chemogenetic inhibition of CRH neurons in the PVN of the hypothalamus is sufficient to decrease seizure susceptibility and depression-like behaviors in chronically epileptic mice. These data suggest that seizure-induced activation of the HPA axis promotes seizure susceptibility and comorbid depression-like behaviors, suggesting that the HPA axis may be a novel target for seizure control.

Effect of Xiaoyaosan on Colon Morphology and Intestinal Permeability in Rats With Chronic Unpredictable Mild Stress

“…Several studies have provided evidence that impaired 5-HT function in the CNS is indeed linked to depression and susceptibility to depression ( Bhagwagar et al., 2002 ; Cowen, 2008 ; Liu et al., 2015 ). The hypothalamic-pituitary-adrenal (HPA) axis is thought to play a mediating role between stress and the development of psychotic symptoms ( Thompson et al., 2007 ), and studies indicate that hyperactivity of the HPA axis is one of the pathogenic mechanisms of depression ( Esmaeili et al., 2018 ; Hooper et al., 2018 ). Moreover, the hypothalamus is the high-level regulatory center of the axis.…”

Sex Differences in the Epilepsies and Associated Comorbidities: Implications for Use and Development of Pharmacotherapies

“…Existing studies suggest that there are sex differences in seizures in experimental animals as highlighted above [for review, see Scharfman and MacLusky (2006)]. In the few studies that have examined associated psychiatric comorbidities, increased anxiety-and depression-like behaviors have been observed in numerous experimental epilepsy models, including both genetic (Aguilar et al, 2018) and acquired epilepsy models (Mazarati et al, 2008;Becker et al, 2015;Hooper et al, 2018;Zeidler et al, 2018). However, none of these studies to date have demonstrated sex differences in anxiety-or depression-like behaviors in epilepsy models, although only a few have looked.…”

“…For example, HPA axis dysfunction, characterized by increased plasma corticosterone and deficits in the dexamethasone suppression test, is positively correlated with depression-like behaviors in an acquired epilepsy model (Mazarati et al, 2009). Similarly, seizure-induced activation of the HPA axis increased seizure frequency and comorbid depression-like behaviors in a preclinical epilepsy model (Hooper et al, 2018). Based on the fact that hypercortisolism is a hallmark feature of depression (Zobel et al, 2004;Kondziella et al, 2007), HPA dysfunction associated with epilepsy has been suggested to contribute to comorbid depression in epilepsy (Pineda et al, 2010).…”

Network Dysfunction in Comorbid Psychiatric Illnesses and Epilepsy

“… 52 In animal models, corticosterone levels are elevated in chronically epileptic mice exhibiting depression-like behaviors, 53 - 55 and blunted activation of the HPA axis improves outcomes in epilepsy including decreased comorbid depression-like behaviors. 56 Neuroendocrine changes, such as elevated levels of stress hormones, have the ability to exert widespread impacts throughout the brain, particularly in limbic regions expressing high levels of mineralocorticoid and glucocorticoid receptors 57 , 58 including the hippocampus and amygdala. In fact, glucocorticoid signaling has been shown to increase neuronal excitability in the hippocampus, 57 , 58 which likely alters network activity and has the potential to negatively impact both epilepsy and psychiatric comorbidities.…”